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Review

Targeting the Renin–Angiotensin–Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins

by
Chien-Ning Hsu
1,2 and
You-Lin Tain
3,4,*
1
Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
2
School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
3
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
4
Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(5), 2298; https://doi.org/10.3390/ijms22052298
Submission received: 6 February 2021 / Revised: 21 February 2021 / Accepted: 23 February 2021 / Published: 25 February 2021
(This article belongs to the Special Issue Renin-Angiotensin-Aldosterone System: Friend or Foe—the Matter of Balance)
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Abstract

:
The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.

1. Introduction

Hypertension and chronic kidney disease (CKD) are highly prevalent diseases around the world. The WHO indicate that one in four men and one in five women have hypertension [1]. CKD affects up to ten percent of the world’s population [2]. Hypertension and CKD are closely interlinked [3], such that CKD is one of the most common causes of secondary hypertension and hypertension is an important factor related to CKD progression. The best-known example is renal artery stenosis, which is characterized by both hypertension and progressive loss of renal function [4]. It was recognized as the prototype of angiotensin-dependent hypertension, contributing to the discovery of the renin–angiotensin-aldosterone system (RAAS) [5].
A growing body of evidence suggests that both hypertension and kidney disease may have their origins in early life [6,7,8]. During kidney development, an exposure to a suboptimal intrauterine environment results in lifelong negative influences on renal structure and function and on renal compensatory mechanisms by so-called renal programming [9,10]. The developing kidney can be programmed by a diversity of early-life insults, leading to hypertension and kidney disease in adulthood. The concept that adverse conditions during organogenesis increase the vulnerability for developing adult diseases is called fetal origins hypothesis [11], more recently named “Developmental Origins of Health and Disease” (DOHaD) [12]. On the other hand, this concept leads to a theoretical shift of therapeutic approach from adult life to earlier stage, namely reprogramming, to potentially reverse disease processes before clinical disease becomes evident [13,14].
Blood pressure (BP) is tightly controlled by very complex networks, including the RAAS, endothelial function, sympathetic nervous system, natriuretic peptides, inflammation and the immune system [15,16,17]. The RAAS serves a counter-regulatory role in the pathogenesis and development of hypertension [17]. Several potential molecular mechanisms involved in developmental programming of hypertension and kidney disease have been addressed, including aberrant RAAS, oxidative stress, nitric oxide (NO) deficiency, gut microbiota dysbiosis, dysregulated nutrient-sensing signals, epigenetic regulation, and reduced nephron number [6,7,8,9,13,14,18,19,20]. Among them, the RAAS not only plays a vital role in the regulation of BP but also closely interacts with other mechanisms. The RAAS is a major hormone cascade composed of different angiotensin peptides with a variety of biological functions mediated by distinct receptors [21]. There are two major pathways in the RAAS: classical and non-classical pathways. The classical RAAS is mainly made up of angiotensin-converting enzyme (ACE), angiotensin (ANG) II, and angiotensin II type 1 receptor (AT1R). Under pathophysiological conditions, the classical RAAS can be activated to trigger vasoconstriction and inflammation, thus promoting hypertension and kidney damage [22]. Conversely, the non-classical RAAS composed of the ACE2-ANG-(1-7)-MAS receptor axis counterbalances the detrimental effects of ANG II signaling.
Of note is that both axes of the RAAS have been linked to fetal programming [23,24]. Although blockade of the classical RAAS provides the rationale for current antihypertensive and renoprotective therapies [25], there is limited data on whether early targeting on the RAAS can prevent hypertension and kidney disease of developmental origins.
In the review, therefore, we present a contemporary update of the RAAS, explaining its role on hypertension and kidney disease of developmental origins and emphasizing its links to other mechanisms. We also highlight the potential reprogramming interventions that target the RAAS for prevention of developmental programming of hypertension and kidney disease. We retrieved related literature from all articles indexed in PubMed/MEDLINE. We used the following keywords and their combinations: “renin”, “angiotensin”, “chronic kidney disease”, “developmental programming”, “DOHaD”, “offspring”, “mother”, “nephrogenesis”, “nephron”, “prorenin receptor”, “aldosterone”, “mineralocorticoid receptor”, “pregnancy”, “progeny”, “reprogramming”, “angiotensinogen”, “angiotensin-converting enzyme”, and “hypertension”. Additional studies were then selected and evaluated based on appropriate references in eligible papers. The last search was conducted on 30 January 2021.

2. RAAS and the Programmed Kidney

2.1. Intrarenal RAAS

The kidney is a principal target for the various components of the RAAS that include prorenin/renin, ANG II, ANG III (ANG-(2–8)), ANG-(1–7), ANG IV (ANG-(3–8)), ANG-(1–9), and aldosterone [26]. Renin starts a cascade of events in the RAAS. The kidney is the only known organ where prorenin to renin conversion occurs [27]. The substrate of the RAS, angiotensinogen (AGT) is released from the liver and is cleaved by renin to generate ANG I. ACE is universally existing in many cell types and tissues/organs. ACE is primarily known for its ability to cleave ANG I to ANG II, while it cleaves not only ANG I but also many other substrates including bradykinin [28]. ANG II stimulates the AT1R to enhance sodium reabsorption and elevate BP [29]. Conversely, ANG II type 2 receptor (AT2R) is the other type of ANG II receptors, which mediates vasodilatation. In the adrenal cortex, ANG II acts to cause the release of aldosterone. Aldosterone promotes sodium retention by stimulating sodium transporter in the distal tubules of the kidneys and, therefore, raises BP. Of note is that the renal RAAS is characterized by the highest tissue concentrations of ANG II [30]. In the kidney, ANG II can also be metabolized to ANG III (ANG-(2–8)) by aminopeptidase A (APA). In turn, ANG III is processed to ANG IV (ANG-(3–8)) by aminopeptidase N (APN) [30].
On the other hand, ACE2, a homologue of ACE, which converts ANG II to ANG-(1–7) or converts ANG I to ANG-(1–9) [31]. ANG-(1–7) induces natriuretic and diuretic effects, in favor of vasodilatation via mediation of MAS receptor [24]. ANG I can also be converted to ANG-(1–7) by the endopeptidase neprilysin (NEP) [30]. In turn, ANG-(1–7) can be processed to (ANG-(2–7)) by APA, and further metabolized by APN to generate ANG-(3–7) [30]. Although most studies of the RAS have mainly focused on ANG II, other peptide fragments Ang-(1-7), ANG III (ANG-(2–8)), ANG IV (ANG-(3–8)), ANG-(2–7), and ANG-(3–7) were identified as potentially bioactive [30]. Since that different peptides in the RAAS could work in concert or in opposition, and that pharmacological alterations of the RAAS result in simultaneous changes of different ANG peptides and compensatory alterations in the abundance/activity of the participating RAAS enzymes, more extensive research work is necessary to understand the complexity of the network of RAAS peptides and how this network system affects renal programming. The processing of various ANG peptides in the RAAS in the kidney is illustrated in Figure 1.

2.2. The Programmed Kidney: Cause for Adult Hypertension and Kindey Disease?

The human kidneys are composed of nephrons ranged from 250,000 to 1.1 million per kidney [32]. Nephron is the functional unit of the kidney, but there is a wide variability with a 10-fold individual difference [32]. The formation of nephrons, namely nephrogenesis, commences at the 9th and continues until 36th week of gestation in humans [33]. The initiation of the kidney development takes place when a ureteric bud outgrowth from the nephric duct invades a group of mesenchymal cells contained within the caudal end of the nephric cord. The elaboration of the ureteric bud is known as branching morphogenesis [34], which leads to the formation of the nephrons and urinary collecting system. The key regulator of primary ureteric bud outgrowth and branching is glial-cell derived neurotrophic factor (GDNF) [35]. Nephron progenitors epithelialize to form the renal vesicle, which elongate to S-shaped body before fully developing into a nephron. There is an exponential increase in nephrons between 18 and 32 weeks. During the third trimester, nephron development is complete between the 32nd and 36th week of gestation [32]. Accordingly, normally nephrogenesis is complete at term. Premature infants thus likely have a reduced nephron endowment at birth. However, nephron number in preterm infants depends on not only gestational age, but also intrauterine environment and perinatal care. Impaired branching morphogenesis could cause low nephron endowment and a wide range of renal maldevelopment, namely congenital anomalies of the kidney and urinary tract (CAKUT).
Important support for renal programming came from the Dutch famine birth cohort study, which revealed that malnutrition during gestation has long-lasting consequences for adult health, including hypertension and kidney disease [36,37]. Several epidemiologic studies have associated prematurity and low birth weight as risk factors for kidney disease and hypertension in later life [38,39,40]. Low birth weight can result from intrauterine growth restriction (IUGR) or preterm birth associated with low nephron number [32,33,41]. A reduced nephron number leads to compensatory glomerular hyperfiltration and glomerular hypertension. This starts a vicious cycle, with a further nephron loss that results in a rising BP, decline in renal function, and may end in CKD.
Nevertheless, the number of nephrons cannot be determined in living humans. Although the use of ferritin-based nanoparticles as targeted magnetic resonance imaging (MRI) contrast agent to measure nephron number in human kidneys has made some progress [42], validation of a method for non-invasive in vivo assessment of nephron endowment deserves greater attention.

2.3. Impact of RAAS in Renal Programming

In the developing kidney, constituents of the RAAS are highly expressed and play a critical role in mediating proper renal morphology and physiological function [43,44]. In rats, all components of RAAS can be detected in the embryonic kidneys from 12 to 17 days of gestation, being higher in fetuses and newborn rats than in adult rats [44]. In humans, drugs interfering with the RAAS (e.g., ACE inhibitors [ACEIs] or angiotensin receptor blockers [ARBs]) have been avoided in pregnant women due to ACEI/ARB fetopathy and renal maldevelopment [45]. Prematurity was associated with an increase in plasma renin and ANG II levels, as well as ACE activity [46]. Animals lacking genes of the RAAS develop markedly abnormal kidneys [47,48]. On the other hand, animals transgenic for RAS genes display hypertension [49]. Blockade of the RAAS with ARB losartan during days 1 to 12 of postnatal life in the rat (during nephrogenesis stage) causes a reduced number of nephrons and hypertension in adulthood [50].
Some risk factors for developing hypertension and kidney disease were assessed in human studies. Nevertheless, these observational studies cannot per se directly establish a causal relationship between the early-life insults and adult disease. Additionally, these human studies do not illuminate molecular mechanisms by which hypertension and kidney disease are created and provide a reprogramming strategy. As a consequence of ethical considerations concerning what is feasible or not in human studies, animal models are of great importance. Given that human studies have many limitations, animal models were established to explore the types of insults driving renal programming, potential mechanisms of renal programming, the vulnerable periods during the kidney development, and potential reprogramming strategy.

3. Animal Models of Renal Programming: Impact of the RAAS

3.1. RAAS-Related Renal Programming in Animal Models

A growing number of animal models are now being established to study hypertension and kidney disease of developmental programming. As reviewed elsewhere [6,7,8,9,10,13,14,18,19,20], several environmental influences in early life that can program the kidney resulting in hypertension and kidney disease in later life, such as maternal malnutrition, maternal illness, maternal smoking, and exposure to medication or environmental toxins. Table 1 summarizes animal studies demonstrating the association between aberrant RAAS, early-life insults, and subsequent hypertension and kidney disease in adult offspring [51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88]. The present review is only restricted to environmental insults happening during the duration of nephrogenesis, with a focus on RAAS-related renal programming.
In this review, animal species range from rats [51,52,53,54,55,56,57,58,59,60,62,63,65,66,67,68,69,71,73,74,75,76,77,79,80,82,83,84,85,86,87], mice [61,72,78,81], rabbits [70], and sheep [64,88]. Rats and mice have been the dominant animal species used in research to study hypertension and kidney disease of developmental origins. Unlike human nephrogenesis, which is completed in utero, renal development in the rodent continues up to 2 weeks after birth [89]. Accordingly, environmental factors not only during pregnancy but also in early lactation period can impair renal development in rodents, resulting in renal programming and adult kidney disease. Table 1 demonstrates the outcomes evaluated in rats ranging from 4 to 90 weeks of age. As one human year equals to two rat weeks in adulthood [90], most outcomes evaluated are equal to human ages from infancy to middle adulthood. Nevertheless, essentially no information exists with regard to large animals to study the impact of RAAS on hypertension and kidney disease of developmental origin.
Table 1 indicates maternal malnutrition is the most common factor related to kidney disease and hypertension of developmental origins. A variety of nutritional insults can cause renal programming, including high sucrose consumption [51], high-fructose diet [52,53], protein restriction [58,59,60,61,62,63], calorie restriction [64], high-fat diet [65,66], high- salt diet [67], and low-salt intake [68]. Second, maternal illness is also interfering with renal programming. These medical conditions during pregnancy include hypertension [69,70], CKD [71], diabetes [72,73], chronodisruption [74], preeclampsia [75], infection [76], placenta insufficiency [77], and hypoxia [78]. Another factor disrupting renal programming is exposure to environmental chemicals or toxins, such as smoking [79,80], caffeine [81], and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [82]. Furthermore, renal programming can be triggered by medications like pyrrolidine dithiocarbamate [83] or glucocorticoid [84,85,86,87,88].
The most common adverse renal outcome of renal programming being studied is hypertension [51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88]. Albuminuria was demonstrated in offspring born of dams with protein restriction [58], diabetes [72], or hypoxia [78]. The glomerular filtration rate (GFR), an index of renal function, was reported as decreased [66,76], unaltered [54,55,59,60], or even increased [58] in different models of renal programming. Additionally, reduced nephron number [57,76,78,79], renal hypertrophy [71], glomerular hypertrophy [78], and tubulointerstitial injury [66,78] are major morphological deficits being reported. These observations indicate that the renal programming does not rely on one particular factor and it displays a wide range of phenotypes.

3.2. Renin, (Pro)renin, and Their Receptor in Renal Programming

Adverse renal outcomes are related to increased renin [53,74,75,78,81,83,85,86] and/or PRR [74,85] expression in most but not all animal models (see Table 1). Renin is mainly synthesized by the juxtaglomerular cells, located in the afferent arterioles of the kidney as preprorenin [91]. The signal peptide is cleaved off during transfer and generate prorenin. By cleavage of a 43-amino acid N-terminal fragment, prorenin is then converted to active renin. The kidney secretes both renin and prorenin into the circulation. Aside from cleaving AGT to generate ANG I, renin binds the PRR. This receptor also binds prorenin. The PRR protein is encoded for the Atp6ap2 (ATPase 6 accessory protein 2). The PRR protein exists in three forms: (1) A full-length 35-39 kDa form consisting of 3 domains, (2) A 28 kDa soluble form, and (3) a truncated form [91].
As the RAAS cascade starts with renin, it raises the question of can we block the RAAS at its point of activation (i.e., renin) to prevent renal programming? The first selective renin inhibitor, aliskiren is noninferior to ACEIs and ARBs for BP reduction and was assessed as an efficient antihypertensive drug [92]. Aliskiren inhibits renin by binding to its catalytic site, thus inhibiting renin and prorenin activity, to block the RAS. However, renin and prorenin levels remain high, which could conceivably induce PRR signaling in an ANG II-independent manner.
Currently, PRR was identified for its multi-functional aspects, including (1) PRR enhances the RAAS by catalyzing ANG I production, (2) PRR induces mitogen-activated protein kinases (MAPK) signal pathway, (3) PRR is required as a subunit of V-ATPase, which transports protons across plasma membrane, and (4) PRR interacts with both the canonical Wnt/β-catenin and non-canonical Wnt/planar cell polarity (PCP) pathways, which are essential for embryonic development [91,93,94].
Many reports have shown that PRR signal pathway can induce ANG II-dependent hypertension [91]. Prorenin overexpression animals exhibited severe hypertension [95]. Unlike other RAS components, PRR knockout mice are lethal or, even tissue-specific, and have a short life expectancy [96], indicating a crucial function of PRR that is (pro)renin-independent. Yet there is currently little evidence about the role of ANG II-independent PRR signal transduction pathway on programmed hypertension.
Our previous report showed that antenatal dexamethasone (DEX) administration increased renin (fold change = 2.41) and PRR (fold change = 2.37) mRNA expression during the stage of nephrogenesis [85]. The increase of renin expression was persistent until 4 months of age and was associated with elevated BP, indicating the impact of PRR on DEX-induced programmed hypertension. Next, we observed that maternal high-fructose increased renal renin expression from 1 day (fold change = 3.05) to 3 months (fold change = 3.38) of age [97]. These findings are consistent with previous studies showing the increases of plasma renin activity in offspring in a diversity of programming models [62,63,68]. Little reliable information currently exists with regard to PRR protein and its downstream signaling in animal models of renal programming. Whether decreased PRR expression could explain the absence of PRR-dependent effects during RAS inhibition remains to be further elucidated [94]. Furthermore, we observed that the downstream signal pathways of PRR, MAPK, and Wnt signal pathways were identified as the significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in the kidney of offspring using next generation RNA sequencing in an NO inhibition model [98]. All of these findings suggested that the PRR pathway might be a therapeutic target for programmed hypertension. The regulatory pathways related to PRR in different programming models are illustrated in the Figure 2.

3.3. Classical RAAS Axis in Renal Programming

Conflicting results exist regarding up- and downregulation of the classical RAAS components (Table 1), due in large part to the wide age range at which offspring were evaluated. In the majority of studies, adult offspring developed hypertension and kidney disease coinciding with increased expression of ACE [64,65,66,72,74,76,82,86] and AT1R [51,54,55,59,62,63,67,69,72,73,74,78,79,80,81,84], and ACE activity [73,77,88].
Very few studies have examined the RAAS in association with renal programming at different developmental stages. In a maternal low protein diet rat model [56], renal AT1R expression was suppressed at birth, whereas its expression was upregulated at 4 weeks of age. In another renal programming model induced by placental insufficiency in the Sprague Dawley rat, adult offspring developed hypertension in conjunction with increased renin and AGT mRNA, as well as increased ACE activity at 16 weeks of age [77]. Conversely, renin and AGT mRNA expression was decreased at birth [77]. Taken together, these findings in renal programming models suggested a transient biphasic response with downregulation of classical RAAS components in neonatal stage that becomes normalized with age. Various early-life insults may disturb this normalization in the adult, so much so that the classical RAS axis is inappropriately activated leading to the rising BP and development of kidney disease in adult offspring. Additionally, aberrant neonatal suppression of the intrarenal RAAS contributes to alterations of renal morphology [9], which is in agreement with studies reporting that blockade of the RAAS by ACEI or ARB [45].
It is noteworthy that aberrant activation of the RAAS can be transgenerational. In a maternal high-fructose diet model [99], elevation of BP was observed in the first- and second-generation offspring, with maximal increases in blood levels of renin, ANG II, and aldosterone in the third-generation offspring. Additionally, maternal high-fructose intake increased the renal mRNA expression of ACE and AT1R over multiple generations of offspring up until the third one. There will be a growing need to better understand whether transgenerational activation of the RAAS has potential impact on other models of renal programming.

3.4. Non-Classical RAAS Axis in Renal Programming

As the non-classical RAAS axis generally opposes the actions of the classical RAAS axis, a reduced tone of the ACE2-ANG-(1-7)-MAS receptor system is considered to contribute to those pathologies as well. Like classical RAAS axis, non-classical axis of the RAAS were also linked to fetal programming [24]. Table 1 shows adult offspring developed hypertension and kidney disease coinciding with downregulated non-classical RAAS pathway in several models of renal programming, including maternal low protein diet [61], maternal CKD [71], maternal diabetes [72], and glucocorticoid exposure model [87,88]. However, the reports were conflicting with increased ACE2 expression in the continuous light exposure model [74].

3.5. Aldosterone in Renal Programming

Aldosterone is the principal regulator of sodium homeostasis. The serum and glucocorticoid-regulated kinase isoform 1 (SGK1) is a key mediator of aldosterone action in the distal nephron to regulate almost all sodium transporters [100]. Compared to other components in the RAAS, less attention has been paid to evaluate the impact of aldosterone in animal models of renal programming. As shown in Table 1, only one report demonstrated that circulating aldosterone level was elevated in 8-week-old offspring born to dams exposed to a low-protein diet [57]. However, renal sodium transporters were studied in several models of renal programming, like antenatal glucocorticoid administration [84,101], low-protein diet [58,102], continuous light exposure model [74], and combined high-fructose and high-salt diet [103]. Various early-life insults have shown that renal programming is associated with increases mRNA levels and protein abundance of several sodium transporters like type 3 sodium hydrogen exchanger (NHE3), Na-K-2Cl cotransporter (NKCC2), Na+/K+ATPase α1 subunit (NaKATPase), and Na+/Cl− cotransporter (NCC). It is noteworthy that SGK1 can be activated by glucocorticoid and salt, except for aldosterone [104]. Therefore, if aberrant sodium transporters in above-mentioned animal models of renal programming are directly regulated by aldosterone or not awaits further clarification. Moreover, emerging evidence shows that fructose-induced hypertension is related to upregulation of the sodium transporter NHE3 and the chloride transporter putative anion transporter 1 (PAT1), to stimulate sodium and chloride absorption [105]. As much of previous work investigating the actions of RAAS has directly studied sodium transporters, there will be a need to better understand the interplay between the RAAS and chloride transporter in hypertension.

4. The Central Role of the RAAS on Mediating Common Mechanisms Underlying Renal Programming

In view of various early-life insults that elicit similar renal outcomes in adult offspring, there might be some common mechanisms of pathogenesis in renal programming. So far, several specific mechanisms were identified to explain renal programming. These mechanisms include aberrant RAAS, oxidative stress, nitric oxide (NO) deficiency, gut microbiota dysbiosis, dysregulated nutrient-sensing signals, epigenetic regulation, and reduced nephron number [6,7,8,9,10,13,18,19,20]. It is important to note that, among these proposed mechanisms, the RAAS is closely connected with others as a hub in determining the renal programming processes. The interplay between the RAAS and other proposed mechanisms underlying renal programming in response to adverse early-life insults is illustrated in Figure 3. Each mechanism will be discussed in turn.

4.1. Oxidative Stress

As reviewed elsewhere [106,107], the key role of oxidative stress implicated in hypertension and kidney disease of developmental origins is supported by many clinical and experimental studies. The imbalance of antioxidants defense system and the reactive oxygen species (ROS) production causes oxidative stress implicating fetal development [108]. Data from multiple animal models indicates oxidative stress involved in renal programming [106,107]. Among them, aberrant RAAS and oxidative stress are both associated with renal programming in models of prenatal DEX exposure [84], maternal high-fructose diet [53], high-fat diet [66], maternal CKD [71], preeclampsia [75], maternal TCDD and dexamethasone exposure [82], and prenatal DEX plus post-weaning high-fat diet [86]. It is well known that ANG II acting via AT1R is a potent activator of NADPH oxidase in the kidney, so much so that it enhances production of ROS implicating in the development of hypertension [109]. On the other hand, ROS-dependent enhancement of AGT plays a role in the progression of diabetic nephropathy [110].
In a model of renal programming, we observed inappropriate activation of the RAAS can be restored by antioxidant therapy [86]. Dimethyl fumarate (DMF) was reported to activate nuclear factor erythroid-derived 2-related factor 2 (Nrf2, a major player in the antioxidant defense) and protect against oxidative stress damage [111]. Our previous work showed DMF administration in pregnancy protects adult offspring against hypertension programmed by antenatal DEX plus postnatal high-fat diet, which was relevant to downregulated mRNA expression of renin, AGT, ACE, and AT1R [86]. Although clinical trials are utilizing Nrf2 inducers to treat CKD, Nrf2 activation was linked to unfavored effects like proteinuria and nephrogenic diabetes insipidus [112,113]. To what extent the Nrf2 activation can be beneficial on CKD, and how Nrf2 and oxidative stress are interconnected with the RAAS, are issues that await further clarification.
Another report showed that the protective effects of melatonin, a potent antioxidant, against programmed hypertension is attributed to increased renal ACE2 level [75]. Moreover, we previously examined the maternal light exposure-induced hypertension model and found maternal melatonin therapy protected offspring against hypertension coincided with increased renal ACE2 expression [74]. Also, melatonin therapy prevented the rise in offspring’s BPs coincided with increased ACE2 protein abundance in a maternal caloric restriction model [114]. These observations suggest that interplay between the RAAS and oxidative stress implicated in renal programming and consequently adverse renal outcomes.

4.2. Nitric Oxide Deficiency

The role of NO deficiency in mediating hypertension and kidney disease of developmental origins has received considerable attention [19,115]. One major cause of NO deficiency is due to increased asymmetric dimethylarginine (ADMA), an endogenous NOS inhibitor [116]. Targeting an ADMA/NO pathway to lower ADMA and restore NO was considered as a reprogramming approach to prevent renal programming and consequently hypertension and kidney disease [19,115].
ANG II can reduce NO bioavailability by promoting oxidative stress, while NO is able to counterbalance the vasoconstrictive effect of ANG II [117]. In a maternal L-NG-Nitro arginine methyl ester (L-NAME, an inhibitor of NO synthase) exposure model, NO depletion caused a rise in BP coinciding with increased mRNA expression of renin and ACE in offspring kidneys [75]. In another model of renal programming, blockade of the RAAS by aliskiren protected adult rat offspring against hypertension programmed by maternal caloric restriction in [118]. The protective effect of aliskiren is not only directed upon the RAAS, but also through regulation of the NO pathway, represented by decreases of plasma ADMA levels and increases of urinary NOx (NO2-+NO3-) levels [118]. Similar to renal programming models, early aliskiren therapy was reported to block the development of hypertension related to decreasing plasma ADMA levels in spontaneously hypertensive rats (SHRs), the most commonly used model of hypertension [119]. As the balance between ADMA/NO pathway and the RAAS plays a decisive role in the pathogenesis of renal programming, there will be a growing need to better understand the mechanisms of the actions of RAAS on renal programming, with a focus on its interplay with NO.

4.3. Reduced Nephron Number

A deficit in the number of nephrons causes high glomerular capillary pressure and glomerular hyperfiltration, consequently leading to further nephron loss in later life [8]. Accordingly, low nephron number was considered as a vital mechanism underlying renal programming. Several epidemiologic studies support that low birth weight and prematurity, two clinical surrogate markers of nephron number, are risk factors for adulthood hypertension and kidney disease [120,121,122]. In rats, adult offspring displayed reduced nephron number when DEX administration was for 2 days on embryonic day 13–14 or 17–18 [101]. These findings indicated the existence of developmental windows of vulnerability to environmental conditions during kidney development. As we mentioned earlier, blockade of the RAAS in lactation, the late stage of nephrogenesis in rodents, leads to reduced nephron number and hypertension in adulthood [50].
Several animal models of renal programming, as shown in Table 1, indicated that various adverse intrauterine conditions can lead to low nephron endowment and aberrant RAAS concurrently, as in the case of maternal protein restriction [56], maternal lipopolysaccharide (LPS) exposure [76], and prenatal hypoxia [78]. Prenatal hypoxia exposure resulted in a reduced nephron number by 25% and elevation of BP in male adult mice offspring, which is related to increases of renal mRNA expression of renin (~2-fold) and AT1R as well as renin concentrations (~50% increase) [78].
However, low nephron endowment, per se, is not essential for hypertension and kidney disease of developmental origins [8]. The roles of RAAS altering the nephron endowment behind the renal programming still remain to be identified, but are the subject of great interest.

4.4. Epigenetic Regulation

Epigenetic regulation is another important mechanism underlying fetal programming [123]. Epigenetic mechanisms consist of DNA methylation, histone modification, and non-coding RNAs (ncRNA). Global DNA methylation patterns in several organs were evaluated in different models of developmental programming, such as maternal low-protein diet [124], maternal smoking [125], and micronutrient deficiency [126]. However, less attention has been paid to the kidney. Aberrant DNA methylation was linked to hypertension of developmental origins [127]. In SHR, increased AT1R expression is relevant to progressive hypo-methylation in the AT1R promoter when hypertension occurs at 20 weeks of age [128]. However, the AT1R gene was reported to be hyper- or hypo-methylated in different models of programmed hypertension [23,129].
Additionally, epigenetic histone modification occurs when the N-terminal tail is subjected to a diversity of post-translational modifications [130]. One of the most frequent epigenetic modifications is histone acetylation, which is catalyzed by histone acetyltransferases (HATs). Conversely, histone deacetylases (HDACs) determine histone deacetylation. The crosstalk between HDAC and the RAAS was proposed to drive uretic bud branching during kidney development [18]. HDACs were reported for the regulated expression of several genes belonging to the RAAS, including AGT, renin, ACE, and AT1R [131]. Our previous study showed that trichostatin A, a HDAC inhibitor, prevented neonatal DEX-induced programmed hypertension accompanied with decreases of AGT, ACE, and ACE2 [87].
The ncRNAs are implicated in several epigenetic processes [132], and microRNAs (miRNAs) are the most commonly studied small ncRNA. In regards to the RAAS-regulated genes, analysis of miRNA binding sites by TargetScan [133] suggested that 368 different miRNA families target RAAS elements, the majority of which share transcripts. In a maternal protein restriction model, renal epithelial-to-mesenchymal transition was associated with a reduced level of miR-200a, miR-141, and miR-429 [134]. Another report demonstrated that mmu-miR-27a and mmu-miR-27b upregulated ACE, while mmu-mir-330 downregulated AT2R in offspring born to dams with protein restriction [135]. However, a single miRNA can regulate numerous mRNAs makes it more challenging to decipher the exact mechanisms involved in renal programming. Additional human and experimental studies are required to clarify the exact nature of the mechanisms behind and to develop potential therapeutic applications.

4.5. Others

There are other reported mechanisms behind renal programming by which the RAAS might act: (1) dysregulated nutrient-sensing signals, (2) gut microbiota dysbiosis, and (3) sex differences. First, early-life nutritional insults can impair nutrient-sensing signals that affect fetal development and consequently program hypertension in later life [136]. Peroxisome proliferator-activated receptor (PPAR), one of the nutrient-sensing signals, can be mediated by other nutrient-sensing signals to regulate the expression of PPAR target genes [137]. Of note is that several PPAR target genes belong to the RAAS components or sodium transporters, like renin and SGK1 [138]. As reviewed elsewhere [138], emerging evidence has indicated that early intervention by PPAR modulators can prevent hypertension of developmental origins. Thus, it is speculated that the RAAS may interact with nutrient-sensing signals to program hypertension and kidney disease.
Second, adverse intrauterine conditions can disturb the gut microbial balance, resulting in subsequent adverse offspring outcomes, including hypertension [139]. Prior research showed that ACE2 exerts a non-catalytic role in gut biology and modulates gut microbiota composition [140]. As dysbiosis of the gut microbiome has been linked to hypertension by modulating the gut RAAS [141], these findings suggested there might be a relationship between gut microbiota and the RAAS underlying the pathogenesis of renal programming, although this remains speculative.
Last, emerging evidence supports sex-dependent differences exist in hypertension and kidney disease of developmental origins [142,143]. It is noteworthy that the RAAS was reported as a sex-specific response to environmental insults [144]. Also, an alteration in the response of the renal transcriptome to diverse insults is sex-dependent [52,145,146]. However, much of the animal models of renal programming, as shown in Table 1, mainly investigating males only instead of both sexes. Thus, there will be a growing need to elucidate the impact of RAAS on sex-dependent mechanisms behind renal programming, and to be able to develop novel sex-specific strategies targeting the RAAS to prevent programmed hypertension and kidney disease of developmental origins in both sexes.
Although the multiple mechanistic links outlined above, the RAAS works as a central connection for hypertension and kidney disease of developmental origins. Better understanding interaction between the RAAS and other common mechanisms as well as targeting on the RAAS to develop reprogramming intervention are key toward early prevention or treating prehypertension and subclinical kidney disease.

5. Targeting on the RAAS as Reprogramming Strategies

Reprogramming strategies targeting the RAAS to prevent the developmental programming of hypertension and kidney disease that were employed in various animal models are listed in Table 2 [52,63,118,119,147,148,149,150,151,152,153,154]. Currently, several therapeutic interventions have been reported, such as renin inhibitor [52,118,119], ACEI [63,147,148,149,150], ARB [118,151,152], AT1R antisense [153], and ACE2 activator [154]. The major protective effects of various RAAS-based interventions on adverse renal outcomes are against hypertension [52,63,118,119,147,148,149,150,151,152,153,154], followed by albuminuria [149], renal dysfunction [150], and renal fibrosis [154]. The reprogramming effects of RAAS-based therapies were examined in rats ranging from 9 weeks to 6 months of age, which are almost equivalent to human ages from childhood to young adulthood. However, most studies focused on males only and did not test different doses. Whether these observed effects appear in a dose- or sex-dependent manner awaits further studies for clarification.
Early blockade of the classical RAAS axis was proposed to reprogram the inappropriately activated RAAS to prevent hypertension and kidney disease of developmental origins. Treating the young offspring with renin inhibitor aliskiren [52,118], ACEI captopril [63], or ARB losartan [118,151] between 2–4 weeks of age are most common therapeutic periods to offset the effects of developmental programming on BP.
To date, aliskiren is the only one renin inhibitor approved for treating hypertension. However, aliskiren cannot prevent the interaction between the PRR and its ligand. Even though beneficial effects for the PRR inhibitory peptide, handle region peptide, and PRO20 [155,156] were reported in animal models, the efficacy in specificity of these peptides is questionable [94]. Thus, it is hoped that designing a specific non-peptide inhibitor of PRR could result in favorable (pro)renin–PRR inhibition in the near future.
All of the prior work investigating reprogramming interventions only studied rats. As nephrogenesis is completed in the second postnatal week in the rat, almost all RAAS-blockade interventions to prevent the hypertension and kidney disease start as early as two weeks after birth. Although AT1R antisense delivery was performed at postnatal day 5 in SHRs [153], its effect on nephron number was not examined yet.
Apart from the classical axis in the RAAS, emerging evidence provides protective roles of non-classical axis in established hypertension and kidney disease, paving the way for new therapeutic approaches [21]. Nevertheless, little attention has been paid to apply this approach on programmed hypertension and kidney disease. According to Table 2, only one study reported administration with diminazene aceturate (DIZE), a putative ACE2 activator, or with ANG -(1–7) during pregnancy could attenuate hypertension and renal fibrosis in adult SHR offspring [154]. Owing to activation of ACE2-ANG-(1-7)-MA axis having therapeutic potential in established hypertension and kidney disease, there is an ongoing need for additional study to elucidate its reprogramming effects in renal programming. What is missing from the literature is a deeper understanding of which the most important component of the RAAS is for the targeted approach and what time is the optimal therapeutic window to be used to prevent hypertension and kidney disease of developmental origins.

6. Conclusions

Current evidence has provided vigorous but incomplete data in regard to the potential therapeutic role of RAAS-based interventions in hypertension and kidney disease of developmental origins. This review affords a brief overview on the various RAAS-based therapies that shows benefits on renal programming, including renin inhibitor, ACEI, ARB, AT1R antisense, and ACE2 activator.
So far, one major unsolved problem is that almost no studies have taken a holistic approach to simultaneous quantify the expression/activity of the entire repertoire of the RAAS components in an experiment. Due to the complex nature of RAAS signaling, the reprogramming effect in response to early-life RAAS-based interventions, either individually or in combination, are incomplete and difficult to predict. Therefore, future work in developing ideal methodology is needed to get a more holistic view of the RAAS and ensure RAAS-based therapy would only apply in the right direction. Moreover, attention will need to be paid to decide the optimal dosage in a sex-dependent manner to maximize the benefit without increasing toxicity prior to clinical translation.
Despite significant progress being made in the availability of a broad range of RAAS-based drugs, less attention has been paid to investigate their reprogramming effects on hypertension and kidney disease. Another challenge is that specific developmental windows for different RAAS-based therapies to reprogram the processes driving hypertension and kidney disease still await further clarification.
For now, our review has taken a step forward by linking RAAS to hypertension and kidney disease of developmental origins, which may yield insights into new RAAS-based interventions for preventing renal programming-related disorders in a clinical setting.

Author Contributions

C.-N.H.: contributed to concept generation, drafting of the manuscript, critical revision of the manuscript, data interpretation, and approval of the article; Y.-L.T.: contributed to drafting of the manuscript, data interpretation, concept generation, critical revision of the manuscript and approval of the article. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Chang Gung Memorial Hospital, Kaohsiung, Taiwan, grants CMRPG8J0251, CMRPG8J0252, CMRPG8J0253, CMRPG8J0891, and CMRPG8J0892.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. World Health Organization. Hypertension. 2019. Available online: https://www.who.int/news-room/fact-sheets/detail/hypertension (accessed on 12 January 2021).
  2. Lozano, R.; Naghavi, M.; Foreman, K.; Lim, S.; Shibuya, K.; Aboyans, V.; Abraham, J.; Adair, T.; Aggarwal, R.; Ahn, S.Y.; et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012, 380, 2095–2128. [Google Scholar] [CrossRef]
  3. Weir, M.R. Hypertension and the kidney: Perspectives on the relationship of kidney disease and cardiovascular disease. Clin. J. Am. Soc. Nephrol. 2009, 4, 2045–2050. [Google Scholar] [CrossRef] [PubMed]
  4. Herrmann, S.M.; Textor, S.C. Renovascular Hypertension. Endocrinol. Metab. Clin. N. Am. 2019, 48, 765–778. [Google Scholar] [CrossRef] [PubMed]
  5. Basso, N.; Terragno, N.A. History about the discovery of the renin-angiotensin system. Hypertension 2001, 38, 1246–1249. [Google Scholar] [CrossRef] [Green Version]
  6. Zandi-Nejad, K.; Luyckx, V.A.; Brenner, B.M. Adult hypertension and kidney disease: The role of fetal programming. Hypertension 2006, 47, 502–508. [Google Scholar] [CrossRef] [Green Version]
  7. Chong, E.; Yosypiv, I.V. Developmental programming of hypertension and kidney disease. Int. J. Nephrol. 2012, 2012, 760580. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Tain, Y.L.; Hsu, C.N. Developmental origins of chronic kidney disease: Should we focus on early life? Int. J. Mol. Sci. 2017, 18, 381. [Google Scholar] [CrossRef] [Green Version]
  9. Kett, M.M.; Denton, K.M. Renal programming: Cause for concern? Am. J. Physiol. Regul. Integr. Comp. Physiol. 2011, 300, R791–R803. [Google Scholar] [CrossRef] [PubMed]
  10. Paixão, A.D.; Alexander, B.T. How the kidney is impacted by the perinatal maternal environment to develop hypertension. Biol. Reprod. 2013, 89, 144. [Google Scholar] [CrossRef]
  11. Barker, D.J. Fetal programming of coronary heart disease. Trends. Endocrinol. Metab. 2002, 13, 364–368. [Google Scholar] [CrossRef]
  12. Haugen, A.C.; Schug, T.T.; Collman, G.; Heindel, J.J. Evolution of DOHaD: The impact of environmental health sciences. J. Dev. Orig. Health Dis. 2015, 6, 55–64. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Tain, Y.L.; Joles, J.A. Reprogramming: A preventive strategy in hypertension focusing on the kidney. Int. J. Mol. Sci. 2016, 17, 23. [Google Scholar] [CrossRef] [Green Version]
  14. Paauw, N.D.; van Rijn, B.B.; Lely, A.T.; Joles, J.A. Pregnancy as a critical window for blood pressure regulation in mother and child: Programming and reprogramming. Acta Physiol. 2017, 219, 241–259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Lee, R.M.; Borkowski, K.R.; Leenen, F.H.; Tsoporis, J.; Coughlin, M. Combined effect of neonatal sympathectomy and adrenal demedullation on blood pressure and vascular changes in spontaneously hypertensive rats. Circ. Res. 1991, 69, 714–721. [Google Scholar] [CrossRef] [Green Version]
  16. Vavřínová, A.; Behuliak, M.; Bencze, M.; Vodička, M.; Ergang, P.; Vaněčková, I.; Zicha, J. Sympathectomy-induced blood pressure reduction in adult normotensive and hypertensive rats is counteracted by enhanced cardiovascular sensitivity to vasoconstrictors. Hypertens. Res. 2019, 42, 1872–1882. [Google Scholar] [CrossRef] [PubMed]
  17. Paz Ocaranza, M.; Riquelme, J.A.; García, L.; Jalil, J.E.; Chiong, M.; Santos, R.A.S.; Lavandero, S. Counter-regulatory renin-angiotensin system in cardiovascular disease. Nat. Rev. Cardiol. 2020, 17, 116–129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Bagby, S.P. Maternal nutrition, low nephron number, and hypertension in later life: Pathways of nutritional programming. J. Nutr. 2007, 137, 1066–1072. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Hsu, C.N.; Tain, Y.L. Regulation of nitric oxide production in the developmental programming of hypertension and kidney disease. Int. J. Mol. Sci. 2019, 20, 681. [Google Scholar] [CrossRef] [Green Version]
  20. Hsu, C.N.; Tain, Y.L. Early-life programming and reprogramming of adult kidney disease and hypertension: The interplay between maternal nutrition and oxidative stress. Int. J. Mol. Sci. 2020, 21, 3572. [Google Scholar] [CrossRef]
  21. Te Riet, L.; van Esch, J.H.; Roks, A.J.; van den Meiracker, A.H.; Danser, A.H. Hypertension: Renin-angiotensin-aldosterone system alterations. Circ. Res. 2015, 116, 960–975. [Google Scholar] [CrossRef]
  22. Forrester, S.J.; Booz, G.W.; Sigmund, C.D.; Coffman, T.M.; Kawai, T.; Rizzo, V.; Scalia, R.; Eguchi, S. Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiol. Rev. 2018, 98, 1627–1738. [Google Scholar] [CrossRef] [PubMed]
  23. Bogdarina, I.; Welham, S.; King, P.J.; Burns, S.P.; Clark, A.J. Epigenetic modification of the renin-angiotensin system in the fetal programming of hypertension. Circ. Res. 2007, 100, 520–526. [Google Scholar] [CrossRef] [Green Version]
  24. Chappell, M.C.; Marshall, A.C.; Alzayadneh, E.M.; Shaltout, H.A.; Diz, D.I. Update on the Angiotensin converting enzyme 2-Angiotensin (1-7)-MAS receptor axis: Fetal programing, sex differences, and intracellular pathways. Front. Endocrinol. 2014, 4, 201. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Cravedi, P.; Ruggenenti, P.; Remuzzi, G. Which antihypertensive drugs are the most nephroprotective and why? Expert Opin. Pharmacother. 2010, 11, 2651–2663. [Google Scholar] [CrossRef]
  26. Wilson, B.A.; Marshall, A.C.; Alzayadneh, E.M.; Chappell, M.C. The ins and outs of angiotensin processing within the kidney. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014, 307, R487–R489. [Google Scholar] [CrossRef] [Green Version]
  27. Stanton, A. Potential of renin inhibition in cardiovascular disease. J. Renin-Angiotensin-Aldosterone Syst. 2003, 4, 6–10. [Google Scholar] [CrossRef] [PubMed]
  28. Shen, X.Z.; Xiao, H.D.; Li, P.; Billet, S.; Lin, C.X.; Fuchs, S.; Bernstein, K.E. Tissue specific expression of angiotensin converting enzyme: A new way to study an old friend. Int. Immunopharmacol. 2008, 8, 171–176. [Google Scholar] [CrossRef] [Green Version]
  29. Navar, L.G.; Kobori, H.; Prieto, M.C.; Gonzalez-Villalobos, R.A. Intrarenal reninangiotensin system in hypertension. Hypertension 2011, 57, 355–362. [Google Scholar] [CrossRef] [Green Version]
  30. Schwacke, J.H.; Spainhour, J.C.; Ierardi, J.L.; Chaves, J.M.; Arthur, J.M.; Janech, M.G.; Velez, J.C. Network modeling reveals steps in angiotensin peptide processing. Hypertension 2013, 61, 690–700. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Donoghue, M.; Hsieh, F.; Baronas, E.; Godbout, K.; Gosselin, M.; Stagliano, N.; Donovan, M.; Woolf, B.; Robison, K.; Jeyaseelan, R.; et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ. Res. 2000, 87, E1–E9. [Google Scholar] [CrossRef] [PubMed]
  32. Bertram, J.F.; Douglas-Denton, R.N.; Diouf, B.; Hughson, M.D.; Hoy, W.E. Human nephron number: Implications for health and disease. Pediatr. Nephrol. 2011, 26, 1529–1533. [Google Scholar] [CrossRef]
  33. Rosenblum, S.; Pal, A.; Reidy, K. Renal development in the fetus and premature infant. Semin. Fetal Neonatal Med. 2017, 22, 58–66. [Google Scholar] [CrossRef] [PubMed]
  34. Shah, M.M.; Sampogna, R.V.; Sakurai, H.; Bush, K.T.; Nigam, S.K. Branching morphogenesis and kidney disease. Development 2004, 131, 1449–1462. [Google Scholar] [CrossRef] [Green Version]
  35. Sainio, K.; Suvanto, P.; Davies, J.; Wartiovaara, J.; Wartiovaara, K.; Saarma, M.; Arumae, U.; Meng, X.; Lindahl, M.; Pachnis, V.; et al. Glial-cell-line-derived neurotrophic factor is required for bud initiation from ureteric epithelium. Development 1997, 124, 4077–4087. [Google Scholar]
  36. Roseboom, T.; de Rooij, S.; Painter, R. The Dutch famine and its long-term consequences for adult health. Early Hum. Dev. 2006, 82, 485–491. [Google Scholar] [CrossRef] [PubMed]
  37. Painter, R.C.; Roseboom, T.J.; van Montfrans, G.A.; Bossuyt, P.M.; Krediet, R.T.; Osmond, C.; Barker, D.J.; Bleker, O.P. Microalbuminuria in adults after prenatal exposure to the Dutch famine. J. Am. Soc. Nephrol. 2005, 16, 189–194. [Google Scholar] [CrossRef]
  38. White, S.L.; Perkovic, V.; Cass, A.; Chang, C.L.; Poulter, N.R.; Spector, T.; Haysom, L.; Craig, J.C.; Salmi, I.A.; Chadban, S.J.; et al. Is low birth weight an antecedent of CKD in later life? A systematic review of observational studies. Am. J. Kidney Dis. 2009, 54, 248–261. [Google Scholar] [CrossRef] [PubMed]
  39. Tain, Y.L.; Luh, H.; Lin, C.Y.; Hsu, C.N. Incidence and risks of congenital anomalies of kidney and urinary tract in newborns: A population-based case-control study in Taiwan. Medicine 2016, 95, e2659. [Google Scholar] [CrossRef] [PubMed]
  40. De Jong, F.; Monuteaux, M.C.; van Elburg, R.M.; Gillman, M.W.; Belfort, M.B. Systematic review and meta-analysis of preterm birth and later systolic blood pressure. Hypertension 2012, 59, 226–234. [Google Scholar] [CrossRef] [Green Version]
  41. Luyckx, V.A.; Brenner, B.M. The clinical importance of nephron mass. J. Am. Soc. Nephrol. 2010, 21, 898–910. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Beeman, S.C.; Cullen-McEwen, L.A.; Puelles, G.; Zhang, M.; Wu, T.; Baldelomar, E.J.; Dowling, J.; Charlton, J.R.; Forbes, M.S.; Ng, A.; et al. MRI-based glomerular morphology and pathology in whole human kidneys. Am. J. Physiol. Ren. Physiol. 2014, 306, F1381–F1390. [Google Scholar] [CrossRef]
  43. Gubler, M.C.; Antignac, C. Renin-angiotensin system in kidney development: Renal tubular dysgenesis. Kidney Int. 2010, 77, 400–406. [Google Scholar] [CrossRef] [Green Version]
  44. Yosypiv, I.V. Renin-angiotensin system in ureteric bud branching morphogenesis: Insights into the mechanisms. Pediatr. Nephrol. 2011, 26, 1499–1512. [Google Scholar] [CrossRef]
  45. Schreuder, M.F.; Bueters, R.R.; Huigen, M.C.; Russel, F.G.; Masereeuw, R.; van den Heuvel, L.P. Effect of drugs on renal development. Clin. J. Am. Soc. Nephrol. 2011, 6, 212–217. [Google Scholar] [CrossRef] [Green Version]
  46. Lee, M.A.; Bohm, M.; Paul, M.; Ganten, D. Tissue renin-angiotensin systems. Their role in cardiovascular disease. Circulation 1993, 87, IV7–IV13. [Google Scholar] [PubMed]
  47. Okubo, S.; Niimura, F.; Matsusaka, T.; Fogo, A.; Hogan, B.L.; Ichikawa, I. Angiotensinogen gene null-mutant mice lack homeostatic regulation of glomerular filtration and tubular reabsorption. Kidney Int. 1998, 53, 617–625. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Tsuchida, S.; Matsusaka, T.; Chen, X.; Okubo, S.; Niimura, F.; Nishimura, H.; Fogo, A.; Utsunomiya, H.; Inagami, T.; Ichikawa, I. Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes. J. Clin. Investig. 1998, 101, 755–760. [Google Scholar] [CrossRef]
  49. Mullins, J.J.; Peters, J.; Ganten, D. Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 1990, 344, 541–544. [Google Scholar] [CrossRef] [PubMed]
  50. Woods, L.L.; Rasch, R. Perinatal ANG II programs adult blood pressure, glomerular number and renal function in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 1998, 275, R1593–R1599. [Google Scholar] [CrossRef] [PubMed]
  51. Wu, L.; Shi, A.; Zhu, D.; Bo, L.; Zhong, Y.; Wang, J.; Xu, Z.; Mao, C. High sucrose intake during gestation increases angiotensin II type 1 receptor-mediated vascular contractility associated with epigenetic alterations in aged offspring rats. Peptides 2016, 86, 133–144. [Google Scholar] [CrossRef]
  52. Hsu, C.N.; Wu, K.L.; Lee, W.C.; Leu, S.; Chan, J.Y.; Tain, Y.L. Aliskiren Administration during Early Postnatal Life Sex-Specifically Alleviates Hypertension Programmed by Maternal High Fructose Consumption. Front. Physiol. 2016, 7, 299. [Google Scholar] [CrossRef]
  53. Tain, Y.L.; Wu, K.L.; Lee, W.C.; Leu, S.; Chan, J.Y. Maternal fructose-intake-induced renal programming in adult male offspring. J. Nutr. Biochem. 2015, 26, 642–650. [Google Scholar] [CrossRef]
  54. Sahajpal, V.; Ashton, N. Increased glomerular angiotensin II binding in rats exposed to a maternal low protein diet in utero. J. Physiol. 2005, 563, 193–201. [Google Scholar] [CrossRef] [PubMed]
  55. Sahajpal, V.; Ashton, N. Renal function and angiotensin AT1 receptor expression in young rats following intrauterine exposure to a maternal low-protein diet. Clin. Sci.(Lond.) 2003, 104, 607–614. [Google Scholar] [CrossRef] [PubMed]
  56. Vehaskari, V.M.; Stewart, T.; Lafont, D.; Soyez, C.; Seth, D.; Manning, J. Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension. Am. J. Physiol. Ren. Physiol. 2004, 287, F262–F267. [Google Scholar] [CrossRef] [PubMed]
  57. Vehaskari, V.M.; Aviles, D.H.; Manning, J. Prenatal programming of adult hypertension in the rat. Kidney Int. 2001, 59, 238–245. [Google Scholar] [CrossRef] [Green Version]
  58. Luzardo, R.; Silva, P.A.; Einicker-Lamas, M.; Ortiz-Costa, S.; do Carmo Mda, G.; Vieira-Filho, L.D.; Paixão, A.D.; Lara, L.S.; Vieyra, A. Metabolic programming during lactation stimulates renal Na+ transport in the adult offspring due to an early impact on local angiotensin II pathways. PLoS ONE 2011, 6, e21232. [Google Scholar] [CrossRef] [Green Version]
  59. Woods, L.L.; Ingelfinger, J.R.; Nyengaard, J.R.; Rasch, R. Maternal protein restriction suppresses the newborn renin-angiotensin system and programs adult hypertension in rats. Pediatr. Res. 2001, 49, 460–467. [Google Scholar] [CrossRef] [Green Version]
  60. Woods, L.L.; Weeks, D.A.; Rasch, R. Programming of adult blood pressure by maternal protein restriction: Role of nephrogenesis. Kidney Int. 2004, 65, 1339–1348. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  61. Goyal, R.; Van-Wickle, J.; Goyal, D.; Longo, L.D. Antenatal maternal low protein diet: ACE-2 in the mouse lung and sexually dimorphic programming of hypertension. BMC Physiol. 2015, 15, 2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Manning, J.; Vehaskari, V.M. Low birth weight-associated adult hypertension in the rat. Pediatr. Nephrol. 2001, 16, 417–422. [Google Scholar] [CrossRef]
  63. Manning, J.; Vehaskari, V.M. Postnatal modulation of prenatally programmed hypertension by dietary Na and ACE inhibition. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005, 288, R80–R84. [Google Scholar] [CrossRef] [PubMed]
  64. Gilbert, J.S.; Lang, A.L.; Grant, A.R.; Nijland, M.J. Maternal nutrient restriction in sheep: Hypertension and decreased nephron number in offspring at 9 months of age. J. Physiol. 2005, 565, 137–147. [Google Scholar] [CrossRef]
  65. Hsu, C.N.; Hou, C.Y.; Chan, J.Y.H.; Lee, C.T.; Tain, Y.L. Hypertension Programmed by Perinatal High-Fat Diet: Effect of Maternal Gut Microbiota-Targeted Therapy. Nutrients 2019, 11, 2908. [Google Scholar] [CrossRef] [Green Version]
  66. Tain, Y.L.; Lin, Y.J.; Sheen, J.M.; Yu, H.R.; Tiao, M.M.; Chen, C.C.; Tsai, C.C.; Huang, L.T.; Hsu, C.N. High Fat Diets Sex-Specifically Affect the Renal Transcriptome and Program Obesity, Kidney Injury, and Hypertension in the Offspring. Nutrients 2017, 9, 357. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Da Silva, A.A.; de Noronha, I.L.; de Oliveira, I.B.; Malheiros, D.M.; Heimann, J.C. Renin-angiotensin system function and blood pressure in adult rats after perinatal salt overload. Nutr. Metab. Cardiovasc. Dis. 2003, 13, 133–139. [Google Scholar] [PubMed]
  68. Battista, M.C.; Oligny, L.L.; St-Louis, J.; Brochu, M. Intrauterine growth restriction in rats is associated with hypertension and renal dysfunction in adulthood. Am. J. Physiol. Endocrinol. Metab. 2002, 283, E124–E131. [Google Scholar] [CrossRef] [Green Version]
  69. Guo, Q.; Feng, X.; Xue, H.; Teng, X.; Jin, S.; Duan, X.; Xiao, L.; Wu, Y. Maternal renovascular hypertensive rats treatment with hydrogen sulfide increased the methylation of AT1b gene in offspring. Am. J. Hypertens. 2017, 30, 1220–1227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  70. Denton, K.M.; Flower, R.L.; Stevenson, K.M.; Anderson, W.P. Adult rabbit offspring of mothers with secondary hypertension have increased blood pressure. Hypertension 2003, 41, 634–639. [Google Scholar] [CrossRef] [Green Version]
  71. Hsu, C.N.; Yang, H.W.; Hou, C.Y.; Chang-Chien, G.P.; Lin, S.; Tain, Y.L. Maternal Adenine-Induced Chronic Kidney Disease Programs Hypertension in Adult Male Rat Offspring: Implications of Nitric Oxide and Gut Microbiome Derived Metabolites. Int. J. Mol. Sci. 2020, 21, 7237. [Google Scholar] [CrossRef]
  72. Chen, Y.W.; Chenier, I.; Tran, S.; Scotcher, M.; Chang, S.Y.; Zhang, S.L. Maternal diabetes programs hypertension and kidney injury in offspring. Pediatr. Nephrol. 2010, 25, 1319–1329. [Google Scholar] [CrossRef] [PubMed]
  73. Wichi, R.B.; Souza, S.B.; Casarini, D.E.; Morris, M.; Barreto-Chaves, M.L.; Irigoyen, M.C. Increased blood pressure in the offspring of diabetic mothers. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005, 288, R1129–R1133. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Tain, Y.L.; Lin, Y.J.; Chan, J.Y.H.; Lee, C.T.; Hsu, C.N. Maternal melatonin or agomelatine therapy prevents programmed hypertension in male offspring of mother exposed to continuous light. Biol. Reprod. 2017, 97, 636–643. [Google Scholar] [CrossRef]
  75. Tain, Y.L.; Lee, C.T.; Chan, J.Y.; Hsu, C.N. Maternal melatonin or N-acetylcysteine therapy regulates hydrogen sulfide-generating pathway and renal transcriptome to prevent prenatal NG-Nitro-L-arginine-methyl ester (L-NAME)-induced fetal programming of hypertension in adult male offspring. Am. J. Obstet. Gynecol. 2016, 215, 636.e1–636.e72. [Google Scholar] [CrossRef] [PubMed]
  76. Hao, X.Q.; Zhang, H.G.; Yuan, Z.B.; Yang, D.L.; Hao, L.Y.; Li, X.H. Prenatal exposure to lipopolysaccharide alters the intrarenal renin-angiotensin system and renal damage in offspring rats. Hypertens. Res. 2010, 33, 76–82. [Google Scholar] [CrossRef] [Green Version]
  77. Grigore, D.; Ojeda, N.B.; Robertson, E.B.; Dawson, A.S.; Huffman, C.A.; Bourassa, E.A.; Speth, R.C.; Brosnihan, K.B.; Alexander, B.T. Placental insufficiency results in temporal alterations in the renin angiotensin system in male hypertensive growth restricted offspring. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007, 293, R804–R811. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Walton, S.L.; Bielefeldt-Ohmann, H.; Singh, R.R.; Li, J.; Paravicini, T.M.; Little, M.H.; Moritz, K.M. Prenatal hypoxia leads to hypertension, renal renin-angiotensin system activation and exacerbates salt-induced pathology in a sex-specific manner. Sci. Rep. 2017, 7, 8241. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Toledo-Rodriguez, M.; Loyse, N.; Bourdon, C.; Arab, S.; Pausova, Z. Effect of prenatal exposure to nicotine on kidney glomerular mass and AT1R expression in genetically diverse strains of rats. Toxicol. Lett. 2012, 213, 228–234. [Google Scholar] [CrossRef]
  80. Xiao, D.; Xu, Z.; Huang, X.; Longo, L.D.; Yang, S.; Zhang, L. Prenatal gender-related nicotine exposure increases blood pressure response to angiotensin II in adult offspring. Hypertension 2008, 51, 1239–1247. [Google Scholar] [CrossRef] [PubMed]
  81. Serapiao-Moraes, D.F.; Souza-Mello, V.; Aguila, M.B.; Mandarim-de-Lacerda, C.A.; Faria, T.S. Maternal caffeine administration leads to adverse effects on adult mice offspring. Eur. J. Nutr. 2013, 52, 1891–1900. [Google Scholar] [CrossRef] [PubMed]
  82. Hsu, C.N.; Lin, Y.J.; Lu, P.C.; Tain, Y.L. Maternal Resveratrol Therapy Protects Male Rat Offspring against Programmed Hypertension Induced by TCDD and Dexamethasone Exposures: Is It Relevant to Aryl Hydrocarbon Receptor? Int. J. Mol. Sci. 2018, 19, 2459. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Canale, D.; Rodrigues, M.V.; Ferreira, D.N.; Machado, F.G.; Veras, M.M.; Malheiros, D.M.; Krieger, J.E.; Fujihara, C.K.; Venturini, G.; Zatz, R. Programmed hypertension in rats treated with a NF-κB inhibitor during nephrogenesis: Renal mechanisms. Hypertens. Res. 2011, 34, 693–700. [Google Scholar] [CrossRef] [Green Version]
  84. Tain, Y.L.; Sheen, J.M.; Chen, C.C.; Yu, H.R.; Tiao, M.M.; Kuo, H.C.; Huang, L.T. Maternal citrulline supplementation prevents prenatal dexamethasone-induced programmed hypertension. Free Radic. Res. 2014, 48, 580–586. [Google Scholar] [CrossRef] [PubMed]
  85. Tain, Y.L.; Chen, C.C.; Sheen, J.M.; Yu, H.R.; Tiao, M.M.; Kuo, H.C.; Huang, L.T. Melatonin attenuates prenatal dexamethasone-induced blood pressure increase in a rat model. J. Am. Soc. Hypertens. 2014, 8, 216–226. [Google Scholar] [CrossRef] [PubMed]
  86. Hsu, C.N.; Lin, Y.J.; Yu, H.R.; Lin, I.C.; Sheen, J.M.; Huang, L.T.; Tain, Y.L. Protection of Male Rat Offspring against Hypertension Programmed by Prenatal Dexamethasone Administration and Postnatal High-Fat Diet with the Nrf2 Activator Dimethyl Fumarate during Pregnancy. Int. J. Mol. Sci. 2019, 20, 3957. [Google Scholar] [CrossRef] [Green Version]
  87. Wu, T.H.; Kuo, H.C.; Lin, I.C.; Chien, S.J.; Huang, L.T.; Tain, Y.L. Melatonin prevents neonatal dexamethasone induced programmed hypertension: Histone deacetylase inhibition. J. Steroid Biochem. Mol. Biol. 2014, 144, 253–259. [Google Scholar] [CrossRef]
  88. Shaltout, H.A.; Figueroa, J.P.; Rose, J.C.; Diz, D.I.; Chappell, M.C. Alterations in circulatory and renal angiotensin-converting enzyme and angiotensin-converting enzyme 2 in fetal programmed hypertension. Hypertension 2009, 53, 404–408. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Hartman, H.A.; Lai, H.L.; Patterson, L.T. Cessation of renal morphogenesis in mice. Dev. Biol. 2007, 310, 379–387. [Google Scholar] [CrossRef] [Green Version]
  90. Sengupta, P. The Laboratory Rat: Relating Its Age with Human’s. Int. J. Prev. Med. 2013, 4, 624–630. [Google Scholar] [PubMed]
  91. Song, R.; Yosypiv, I.V. (Pro)renin Receptor in Kidney Development and Disease. Int. J. Nephrol. 2011, 2011, 247048. [Google Scholar] [CrossRef] [Green Version]
  92. Sanoski, C.A. Aliskiren: An oral direct renin inhibitor for the treatment of hypertension. Pharmacotherapy 2009, 29, 193–212. [Google Scholar] [CrossRef] [PubMed]
  93. Nguyen, G. Renin, (pro)renin and receptor: An update. Clin. Sci. 2011, 120, 169–178. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Krop, M.; Lu, X.; Danser, A.H.; Meima, M.E. The (pro)renin receptor. A decade of research: What have we learned? Pflüg. Arch. 2013, 465, 87–97. [Google Scholar] [CrossRef] [Green Version]
  95. Mercure, C.; Prescott, G.; Lacombe, M.J.; Silversides, D.W.; Reudelhuber, T.L. Chronic increases in circulating prorenin are not associated with renal or cardiac pathologies. Hypertension 2009, 53, 1062–1069. [Google Scholar] [CrossRef] [Green Version]
  96. Riediger, F.; Quack, I.; Qadri, F.; Hartleben, B.; Park, J.K.; Potthoff, S.A.; Sohn, D.; Sihn, G.; Rousselle, A.; Fokuhl, V.; et al. Prorenin receptor is essential for podocyte autophagy and survival. J. Am. Soc. Nephrol. 2011, 22, 2193–2202. [Google Scholar] [CrossRef] [PubMed]
  97. Chao, Y.M.; Tain, Y.L.; Leu, S.; Wu, K.L.; Lee, W.C.; Chan, J.Y. Developmental programming of the metabolic syndrome: Next-generation sequencing analysis of transcriptome expression in a rat model of maternal high fructose intake. Sheng Li Xue Bao 2016, 68, 557–567. [Google Scholar]
  98. Tain, Y.L.; Huang, L.T.; Lee, C.T.; Chan, J.Y.; Hsu, C.N. Maternal citrulline supplementation prevents prenatal NG-nitro-L-arginine-methyl ester (L-NAME)-induced programmed hypertension in rats. Biol. Reprod. 2015, 92, 1–7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Seong, H.Y.; Cho, H.M.; Kim, M.; Kim, I. Maternal High-Fructose Intake Induces Multigenerational Activation of the Renin-Angiotensin-Aldosterone System. Hypertension 2019, 74, 518–525. [Google Scholar] [CrossRef] [PubMed]
  100. Lou, Y.; Zhang, F.; Luo, Y.; Wang, L.; Huang, S.; Jin, F. Serum and Glucocorticoid Regulated Kinase 1 in Sodium Homeostasis. Int. J. Mol. Sci. 2016, 17, 1307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Ortiz, L.A.; Quan, A.; Weinberg, A.; Baum, M. Effect of prenatal dexamethasone on rat renal development. Kidney Int. 2001, 59, 1663–1669. [Google Scholar] [CrossRef] [Green Version]
  102. Dagan, A.; Kwon, H.M.; Dwarakanath, V.; Baum, M. Effect of renal denervation on prenatal programming of hypertension and renal tubular transporter abundance. Am. J. Physiol. Ren. Physiol. 2008, 295, F29–F34. [Google Scholar] [CrossRef] [Green Version]
  103. Tain, Y.L.; Lee, W.C.; Leu, S.; Wu, K.; Chan, J. High salt exacerbates programmed hypertension in maternal fructose-fed male offspring. Nutr. Metab. Cardiovasc. Dis. 2015, 25, 1146–1151. [Google Scholar] [CrossRef]
  104. Vallon, V.; Lang, F. New insights into the role of serum- and glucocorticoid-inducible kinase SGK1 in the regulation of renal function and blood pressure. Curr. Opin. Nephrol. Hypertens. 2005, 14, 59–66. [Google Scholar] [CrossRef]
  105. Klein, A.V.; Kiat, H. The mechanisms underlying fructose-induced hypertension: A review. J. Hypertens. 2015, 33, 912–920. [Google Scholar] [CrossRef] [Green Version]
  106. Hsu, C.N.; Tain, Y.L. Early Origins of Hypertension: Should Prevention Start Before Birth Using Natural Antioxidants? Antioxidants 2020, 9, 1034. [Google Scholar] [CrossRef]
  107. Hsu, C.N.; Tain, Y.L. Developmental Origins of Kidney Disease: Why Oxidative Stress Matters? Antioxidants 2021, 10, 33. [Google Scholar] [CrossRef]
  108. Thompson, L.P.; Al-Hasan, Y. Impact of oxidative stress in fetal programming. J. Pregnancy 2012, 2012, 582748. [Google Scholar] [CrossRef] [PubMed]
  109. Araujo, M.; Wilcox, C.S. Oxidative stress in hypertension: Role of the kidney. Antioxid. Redox Signal. 2014, 20, 74–101. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Kamiyama, M.; Urushihara, M.; Morikawa, T.; Konishi, Y.; Imanishi, M.; Nishiyama, A.; Kobori, H. Oxidative stress/angiotensinogen/renin-angiotensin system axis in patients with diabetic nephropathy. Int. J. Mol. Sci. 2013, 14, 23045–23062. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Vomund, S.; Schäfer, A.; Parnham, M.J.; Brüne, B.; Von Knethen, A. Nrf2, the Master Regulator of Anti-Oxidative Responses. Int. J. Mol. Sci. 2017, 18, 2772. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Rush, B.M.; Bondi, C.D.; Stocker, S.D.; Barry, K.M.; Small, S.A.; Ong, J.; Jobbagy, S.; Stolz, D.B.; Bastacky, S.I.; Chartoumpekis, D.V.; et al. Genetic or pharmacologic Nrf2 activation increases proteinuria in chronic kidney disease in mice. Kidney Int. 2021, 99, 102–116. [Google Scholar] [CrossRef] [PubMed]
  113. Suzuki, T.; Seki, S.; Hiramoto, K.; Naganuma, E.; Kobayashi, E.H.; Yamaoka, A.; Baird, L.; Takahashi, N.; Sato, H.; Yamamoto, M. Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus. Nat. Commun. 2017, 8, 14577. [Google Scholar] [CrossRef] [Green Version]
  114. Tain, Y.L.; Huang, L.T.; Hsu, C.N.; Lee, C.T. Melatonin therapy prevents programmed hypertension and nitric oxide deficiency in offspring exposed to maternal caloric restriction. Oxid. Med. Cell. Longev. 2014, 2014, 283180. [Google Scholar] [CrossRef] [PubMed]
  115. Tain, Y.L.; Hsu, C.N. Targeting on asymmetric dimethylarginine related nitric oxide-reactive oxygen species imbalance to reprogram the development of hypertension. Int. J. Mol. Sci. 2016, 17, 2020. [Google Scholar] [CrossRef] [Green Version]
  116. Tain, Y.L.; Hsu, C.N. Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA). Toxins 2017, 9, 92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Schulman, I.H.; Zhou, M.S.; Raij, L. Interaction between nitric oxide and angiotensin II in the endothelium: Role in atherosclerosis and hypertension. J. Hypertens. 2006, 24, S45–S50. [Google Scholar] [CrossRef] [PubMed]
  118. Tain, Y.L.; Hsu, C.N.; Lin, C.Y.; Huang, L.T.; Lau, Y.T. Aliskiren prevents hypertension and reduces asymmetric dimethylarginine in young spontaneously hypertensive rats. Eur. J. Pharmacol. 2011, 670, 561–565. [Google Scholar] [CrossRef]
  119. Hsu, C.N.; Lee, C.T.; Huang, L.T.; Tain, Y.L. Aliskiren in early postnatal life prevents hypertension and reduces asymmetric dimethylarginine in offspring exposed to maternal caloric restriction. J. Renin-Angiotensin-Aldosterone Syst. 2015, 16, 506–513. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  120. Kanda, T.; Murai-Takeda, A.; Kawabe, H.; Itoh, H. Low birth weight trends: Possible impacts on the prevalences of hypertension and chronic kidney disease. Hypertens. Res. 2020, 43, 859–868. [Google Scholar] [CrossRef] [PubMed]
  121. Luyckx, V.A.; Brenner, B.M. Birth weight, malnutrition and kidney-associated outcomes—A global concern. Nat. Rev. Nephrol. 2015, 11, 135–149. [Google Scholar] [CrossRef] [PubMed]
  122. Starr, M.C.; Hingorani, S.R. Prematurity and future kidney health: The growing risk of chronic kidney disease. Curr. Opin. Pediatr. 2018, 30, 228–235. [Google Scholar] [CrossRef]
  123. Bianco-Miotto, T.; Craig, J.M.; Gasser, Y.P.; van Dijk, S.J.; Ozanne, S.E. Epigenetics and DOHaD: From basics to birth and beyond. J. Dev. Orig. Health Dis. 2017, 8, 513–519. [Google Scholar] [CrossRef] [PubMed]
  124. Rees, W.D.; Hay, S.M.; Brown, D.S.; Antipatis, C.; Palmer, R.M. Maternal protein deficiency causes hypermethylation of DNA in the livers of rat fetuses. J. Nutr. 2000, 130, 1821–1826. [Google Scholar] [CrossRef] [Green Version]
  125. Suter, M.; Ma, J.; Harris, A.; Patterson, L.; Brown, K.A.; Shope, C.; Showalter, L.; Abramovici, A.; Aagaard-Tillery, K.M. Maternal tobacco use modestly alters correlated epigenome-wide placental DNA methylation and gene expression. Epigenetics 2011, 6, 1284–1294. [Google Scholar] [CrossRef] [Green Version]
  126. Sable, P.; Randhir, K.; Kale, A.; Chavan-Gautam, P.; Joshi, S. Maternal micronutrients and brain global methylation patterns in the offspring. Nutr. Neurosci. 2015, 18, 30–36. [Google Scholar] [CrossRef] [PubMed]
  127. Han, L.; Liu, Y.; Duan, S.; Perry, B.; Li, W.; He, Y. DNA methylation and hypertension: Emerging evidence and challenges. Brief Funct. Genom. 2016, 15, 460–469. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Pei, F.; Wang, X.; Yue, R.; Chen, C.; Huang, J.; Huang, J.; Li, X.; Zeng, C. Differential expression and DNA methylation of angiotensin type 1A receptors in vascular tissues during genetic hypertension development. Mol. Cell. Biochem. 2015, 402, 1–8. [Google Scholar] [CrossRef] [PubMed]
  129. Bogdarina, I.G.; King, P.J.; Clark, A.J. Characterization of the angiotensin (AT1b) receptor promoter and its regulation by glucocorticoids. J. Mol. Endocrinol. 2009, 43, 73–80. [Google Scholar] [CrossRef] [Green Version]
  130. Raftopoulos, L.; Katsi, V.; Makris, T.; Tousoulis, D.; Stefanadis, C.; Kallikazaros, I. Epigenetics, the missing link in hypertension. Life Sci. 2015, 129, 22–26. [Google Scholar] [CrossRef]
  131. Song, R.; Van Buren, T.; Yosypiv, I.V. Histone deacetylases are critical regulators of the renin-angiotensin system during ureteric bud branching morphogenesis. Pediatr. Res. 2010, 67, 573–578. [Google Scholar] [CrossRef] [Green Version]
  132. Costa, F.F. Non-coding RNAs, epigenetics and complexity. Gene 2008, 410, 9–17. [Google Scholar] [CrossRef] [PubMed]
  133. Agarwal, V.; Bell, G.W.; Nam, J.W.; Bartel, D.P. Predicting effective microRNA target sites in mammalian mRNAs. Elife 2015, 4, e05005. [Google Scholar] [CrossRef]
  134. SeneLde, B.; Mesquita, F.F.; deMoraes, L.N.; Santos, D.C.; Carvalho, R.; Gontijo, J.A.; Boer, P.A. Involvement of renal corpuscle microRNA expression on epithelial-to-mesenchymal transition in maternal low protein diet in adult programmed rats. PLoS ONE 2013, 8, e71310. [Google Scholar]
  135. Goyal, R.; Goyal, D.; Leitzke, A.; Gheorghe, C.P.; Longo, L.D. Brain renin-angiotensin system: Fetal epigenetic programming by maternal protein restriction during pregnancy. Reprod. Sci. 2010, 17, 227–238. [Google Scholar] [CrossRef] [PubMed]
  136. Tain, Y.L.; Hsu, C.N. Interplay between oxidative stress and nutrient sensing signaling in the developmental origins of cardiovascular disease. Int. J. Mol. Sci. 2017, 18, 841. [Google Scholar] [CrossRef]
  137. Efeyan, A.; Comb, W.C.; Sabatini, D.M. Nutrient-sensing mechanisms and pathways. Nature 2015, 517, 302–310. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  138. Tain, Y.L.; Hsu, C.N.; Chan, J.Y. PPARs link early life nutritional insults to later programmed hypertension and metabolic syndrome. Int. J. Mol. Sci. 2015, 17, 20. [Google Scholar] [CrossRef] [Green Version]
  139. Chu, D.M.; Meyer, K.M.; Prince, A.L.; Aagaard, K.M. Impact of maternal nutrition in pregnancy and lactation on offspring gut microbial composition and function. Gut Microbes 2016, 7, 459–470. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  140. Oliveira Andrade, J.M.; de Farias Lelis, D.; Mafra, V.; Cota, J. The Angiotensin Converting Enzyme 2 (ACE2), Gut Microbiota, and Cardiovascular Health. Protein Pept. Lett. 2017, 24, 827–832. [Google Scholar] [CrossRef]
  141. Richards, E.M.; Pepine, C.J.; Raizada, M.K.; Kim, S. The Gut, Its Microbiome, and Hypertension. Curr. Hypertens. Rep. 2017, 19, 36. [Google Scholar] [CrossRef] [Green Version]
  142. Gilbert, J.S.; Nijland, M.J. Sex differences in the developmental origins of hypertension and cardiorenal disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008, 295, R1941–R1952. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Tomat, A.L.; Salazar, F.J. Mechanisms involved in developmental programming of hypertension and renal diseases. Gender differences. Horm. Mol. Biol. Clin. Investig. 2014, 18, 63–77. [Google Scholar] [CrossRef]
  144. Hilliard, L.M.; Sampson, A.K.; Brown, R.D.; Denton, K.M. The “his and hers” of the renin-angiotensin system. Curr. Hypertens. Rep. 2013, 15, 71–79. [Google Scholar] [CrossRef] [PubMed]
  145. Kwekel, J.C.; Desai, V.G.; Moland, C.L.; Vijay, V.; Fuscoe, J.C. Sex differences in kidney gene expression during the life cycle of F344 rats. Biol. Sex Differ. 2013, 4, 14. [Google Scholar] [CrossRef] [Green Version]
  146. Tain, Y.L.; Wu, M.S.; Lin, Y.J. Sex differences in renal transcriptome and programmed hypertension in offspring exposed to prenatal dexamethasone. Steroids 2016, 115, 40–46. [Google Scholar] [CrossRef] [PubMed]
  147. Zicha, J.; Dobesová, Z.; Kunes, J. Late blood pressure reduction in SHR subjected to transient captopril treatment in youth: Possible mechanisms. Physiol. Res. 2008, 57, 495–498. [Google Scholar] [PubMed]
  148. Sherman, R.C.; Langley-Evans, S.C. Antihypertensive treatment in early postnatal life modulates prenatal dietary influences upon blood pressure in the rat. Clin. Sci. (Lond.) 2000, 98, 269–275. [Google Scholar] [CrossRef]
  149. Mansuri, A.; Elmaghrabi, A.; Legan, S.K.; Gattineni, J.; Baum, M. Transient Exposure of Enalapril Normalizes Prenatal Programming of Hypertension and Urinary Angiotensinogen Excretion. PLoS ONE 2015, 10, e0146183. [Google Scholar] [CrossRef]
  150. Harrap, S.B.; Nicolaci, J.A.; Doyle, A.E. Persistent effects on blood pressure and renal haemodynamics following chronic angiotensin converting enzyme inhibition with perindopril. Clin. Exp. Pharmacol. Physiol. 1986, 13, 753–765. [Google Scholar] [CrossRef] [PubMed]
  151. Sherman, R.C.; Langley-Evans, S.C. Early administration of angiotensin-converting enzyme inhibitor captopril, prevents the development of hypertension programmed by intrauterine exposure to a maternal low-protein diet in the rat. Clin. Sci. (Lond.) 1998, 94, 373–381. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Klimas, J.; Olvedy, M.; Ochodnicka-Mackovicova, K.; Kruzliak, P.; Cacanyiova, S.; Kristek, F.; Krenek, P.; Ochodnicky, P. Perinatally administered losartan augments renal ACE2 expression but not cardiac or renal Mas receptor in spontaneously hypertensive rats. J. Cell. Mol. Med. 2015, 19, 1965–1974. [Google Scholar] [CrossRef] [PubMed]
  153. Iyer, S.N.; Lu, D.; Katovich, M.J.; Raizada, M.K. Chronic control of high blood pressure in the spontaneously hypertensive rat by delivery of angiotensin type 1 receptor antisense. Proc. Natl. Acad. Sci. USA 1996, 93, 9960–9965. [Google Scholar] [CrossRef] [Green Version]
  154. Bessa, A.S.M.; Jesus, É.F.; Nunes, A.D.C.; Pontes, C.N.R.; Lacerda, I.S.; Costa, J.M.; Souza, E.J.; Lino-Júnior, R.S.; Biancardi, M.F.; Dos Santos, F.C.A.; et al. Stimulation of the ACE2/Ang-(1–7)/Mas axis in hypertensive pregnant rats attenuates cardiovascular dysfunction in adult male offspring. Hypertens. Res. 2019, 42, 1883–1893. [Google Scholar] [CrossRef] [PubMed]
  155. Ichihara, A.; Hayashi, M.; Kaneshiro, Y.; Suzuki, F.; Nakagawa, T.; Tada, Y.; Koura, Y.; Nishiyama, A.; Okada, H.; Uddin, M.N.; et al. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin. J. Clin. Investig. 2004, 114, 1128–1135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Li, W.; Sullivan, M.N.; Zhang, S.; Worker, C.J.; Xiong, Z.; Speth, R.C.; Feng, Y. Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension. Hypertension 2015, 65, 352–361. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Schema outlining the renin-angiotensin-aldosterone system cascade including the renal effects of receptor stimulation. AGT, angiotensinogen; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; ANG, angiotensin; ANG I, angiotensin I; ANG II, angiotensin II; ANG III, ANG-(2–8); ANG IV, ANG-(3–8); APA, aminopeptidase A; APN, aminopeptidase N; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II receptor; MAS, angiotensin-(1–7) receptor MAS; MR, mineralocorticoid receptor; NEP, neutral endopeptidase; PEP, prolyl endopeptidase; PRR, (Pro)renin- receptor.
Figure 1. Schema outlining the renin-angiotensin-aldosterone system cascade including the renal effects of receptor stimulation. AGT, angiotensinogen; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; ANG, angiotensin; ANG I, angiotensin I; ANG II, angiotensin II; ANG III, ANG-(2–8); ANG IV, ANG-(3–8); APA, aminopeptidase A; APN, aminopeptidase N; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II receptor; MAS, angiotensin-(1–7) receptor MAS; MR, mineralocorticoid receptor; NEP, neutral endopeptidase; PEP, prolyl endopeptidase; PRR, (Pro)renin- receptor.
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Figure 2. Flow diagram of identified pathways from previous models of renal programming, whereby (pro)renin–PRR pathway is linked to programmed hypertension and kidney disease via ANG II-dependent and –independent effects. AGT, angiotensinogen; ANG I, angiotensin I; ANG II, angiotensin II; MAPK, mitogen-activated protein kinases; NO, nitric oxide; RAAS, renin-angiotensin-aldosterone system, ⊕, enhance.
Figure 2. Flow diagram of identified pathways from previous models of renal programming, whereby (pro)renin–PRR pathway is linked to programmed hypertension and kidney disease via ANG II-dependent and –independent effects. AGT, angiotensinogen; ANG I, angiotensin I; ANG II, angiotensin II; MAPK, mitogen-activated protein kinases; NO, nitric oxide; RAAS, renin-angiotensin-aldosterone system, ⊕, enhance.
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Figure 3. Schema outlining the central role of RAAS on mediating other mechanisms in the kidney leading to hypertension and kidney disease of developmental origins in response to a variety of maternal insults. Target on the RAAS-based interventions could be reprogramming strategies to prevent hypertension and kidney in adult offspring. NO, nitric oxide; RAAS, renin-angiotensin-aldosterone system.
Figure 3. Schema outlining the central role of RAAS on mediating other mechanisms in the kidney leading to hypertension and kidney disease of developmental origins in response to a variety of maternal insults. Target on the RAAS-based interventions could be reprogramming strategies to prevent hypertension and kidney in adult offspring. NO, nitric oxide; RAAS, renin-angiotensin-aldosterone system.
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Table
Table 1. Renal programming related to aberrant renin-angiotensin-aldosterone system (RAAS) in animal models. Studies tabulated according to animal models, species, and age at evaluation. CKD, chronic kidney disease; L-NAME, L-NG-Nitro arginine methyl ester; LPS, lipopolysaccharide; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; PDTC, pyrrolidine dithiocarbamate; DEX, dexamethasone; Cr, creatinine; SD, Sprague Dawley; SHR, spontaneously hypertensive rat; M, male; F, female; BP, blood pressure; GFR, glomerular filtration rate; ↑, increased; ↓, decreased; ↔, unaltered; PRR, (pro)renin receptor; PRA, plasma renin activity; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; AGT, angiotensinogen; AT1R, angiotensin type 1 receptor; AT2R, angiotensin type 2 receptor.
Table 1. Renal programming related to aberrant renin-angiotensin-aldosterone system (RAAS) in animal models. Studies tabulated according to animal models, species, and age at evaluation. CKD, chronic kidney disease; L-NAME, L-NG-Nitro arginine methyl ester; LPS, lipopolysaccharide; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; PDTC, pyrrolidine dithiocarbamate; DEX, dexamethasone; Cr, creatinine; SD, Sprague Dawley; SHR, spontaneously hypertensive rat; M, male; F, female; BP, blood pressure; GFR, glomerular filtration rate; ↑, increased; ↓, decreased; ↔, unaltered; PRR, (pro)renin receptor; PRA, plasma renin activity; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; AGT, angiotensinogen; AT1R, angiotensin type 1 receptor; AT2R, angiotensin type 2 receptor.
Animal ModelsIntervention PeriodSpecies/GenderAge at EvaluationRenal PhenotypeAlterations of the RAASRef.
20% w/v sucrose in drinking waterPregnancySD rat/M90 weeks↑BP↑AT1R mRNA and protein [51]
High-fructose diet, 60%Pregnancy and LactationSD rat/M12 weeks↑BP↓AT2R mRNA[52]
High-fructose diet, 60%Pregnancy and LactationSD rat/M12 weeks↑BP, altered renal transcriptome↑Renin mRNA[53]
Protein restriction, 9%PregnancySD rat/M4 weeks↑BP, ↔GFR↑AT1R protein and ↓AT2R protein, ↔ANG level [54,55]
Protein restriction, 6%PregnancySD rat/M and F4 weeks↑BP↓AT1R and AT2R protein at birth; ↑AT1R and AT2R protein at 4 wk[56]
Protein restriction, 6%PregnancySD rat/M and F8 weeks↑BP, ↓nephron number↓PRA, ↓AT1R mRNA and protein, ↑Aldosterone[57]
Protein restriction, 8%LactationWistar rat/M150 days↑BP, ↑GFR, ↑Proteinuria↑AT1R protein and↓AT2R protein[58]
Protein restriction, 8.5%PregnancySD rat/M22 weeks↑BP, ↔GFR↓renin mRNA and protein; and ↓renal ANG II level at 1–5 days of age [59,60]
Protein restriction, 9%1 week before conception and throughout pregnancyFVB/NJ mouse/F24 weeks↑BP↓ACE2 protein[61]
Protein restrictionSecond half of pregnancySD and Wistar rat/M and F11 months↑BP↑PRA, ↑AT1R mRNA and protein[62,63]
50% caloric restrictionDay 28 to day 78 of gestationSheep/M and F9 months↑BP↑ACE protein[64]
High-fat diet, 58%Pregnancy and LactationSD rat/M16 weeks↑BP↑AGT and ACE mRNA, and↑AT1R protein[65]
High-fat diet, 58%5 weeks before the delivery and throughout pregnancy and lactationSD rat/M and F6 months↔BP, ↓GFR, ↑glomerular injury, ↑tubulointerstitial injury, altered renal transcriptome↑ACE and AT1R mRNA in F[66]
High-salt diet, 8% PregnancyWistar rat/F12 weeks↑BP↑ANG II[67]
0.03% low-salt dietLast 7 days of pregnancySD rat/M and F12 weeks↑BP↑PRA[68]
Maternal renovascular hypertensionPregnancySD rat/M16 weeks↑BP↑AT1R protein[69]
Maternal renovascular hypertensionPregnancyRabbit/F30 weeks↑BP↓PRA at 10 week[70]
Maternal adenine-induced CKDPregnancy and lactationSD rat/M12 weeks↑BP, renal hypertrophy↓AT2R and MAS receptor mRNA[71]
Maternal streptozotocin-induced diabetesPregnancyC57BL/6 mouse/M20 weeks↑BP, microalbuminuria↑AT1R and ACE mRNA, ↓ACE2 mRNA[72]
Maternal streptozotocin-induced diabetesPregnancyWistar rat/M2 months↑BP↑ACE activity[73]
Continuous light exposurePregnancy and lactationSD rat/M12 weeks↑BP↑Renin, PRR,
AGT, ACE, ACE2, and AT1R mRNA		[74]
Maternal L-NAME exposurePregnancySD rat/M12 weeks↑BP↑Renin and ACE mRNA[75]
Maternal LPS exposurePregnancySD rat/M and F24 weeks↑BP, ↓nephron number and GFR↑ACE mRNA[76]
Placenta insufficiencyPregnancySD rat/M16 weeks↑BP↓Renin and AGT mRNA at birth, ↑Renin and AGT mRNA, ↑ACE activity at 16 week[77]
Prenatal hypoxiaFrom embryonic day 14.5 until birthCD1 mouse/M and F12 monthsMicroalbuminuria, glomerular hypertrophy and renal fibrosis, ↓nephron number↑Renin and AT1R mRNA[78]
Maternal nicotine exposurePregnancySHR/M9 weeks↑BP, ↓Glomerular mass↑AT1R mRNA[79]
Maternal nicotine exposurePregnancySD rat/M5 months↑BP↑AT1R protein, ↓AT2R protein[80]
Maternal caffeine exposurePregnancyC57BL/6 mouse/M3 months↑BP↑Renin and AT1R mRNA[81]
Maternal TCDD and dexamethasone exposurePregnancy and LactationSD rat/M16 weeks↑BP↑ACE mRNA[82]
Neonatal PDTC administrationLactationMunich-Wistar rat/M10 months↑BP↑Renin and AGT mRNA at 3 month; ↓Renin and AGT at 10 month[83]
Prenstal DEX exposurePregnancySD rat/M16 weeks↑BP↑AGT and AT1R mRNA[84]
Prenstal DEX exposurePregnancySD rat/M16 weeks↑BP↑Renin and PRR mRNA[85]
Prenatal DEX plus post-weaning high-fat dietPregnancySD rat/M16 weeks↑BP↑Renin and ACE mRNA[86]
Neonatal DEX administrationDay 1 to day 3 after birthSD rat/M16 weeks↑BP↓AGT, ACE, and ACE2 mRNA[87]
Prenatal betamethasone exposure2 doses, 24 h apart at gestational day 80Sheep/M1.8 years↑BP↑ACE activity, ↓ACE2 activity[88]
Table
Table 2. Interventions targeting on the RAAS to prevent hypertension and kidney disease of developmental origins.Studies tabulated according to types of intervention, animal model, species, and age at evaluation. SD, Sprague Dawley; SHR, spontaneously hypertensive rat; M, male; F, female; ACE2, angiotensin-converting enzyme 2; AGT, angiotensinogen; Ang II, angiotensin II; AT1R, angiotensin type 1 receptor; MAS receptor, ANG-(1–7) receptor MAS.
Table 2. Interventions targeting on the RAAS to prevent hypertension and kidney disease of developmental origins.Studies tabulated according to types of intervention, animal model, species, and age at evaluation. SD, Sprague Dawley; SHR, spontaneously hypertensive rat; M, male; F, female; ACE2, angiotensin-converting enzyme 2; AGT, angiotensinogen; Ang II, angiotensin II; AT1R, angiotensin type 1 receptor; MAS receptor, ANG-(1–7) receptor MAS.
InterventionAnimal ModelSpecies/GenderAge at EvaluationEffectsProtective MechanismRef.
Renin inhibitor
Aliskiren (10 or 30 mg/kg/day) between 4–10 weeks of ageGenetic hypertension modelSHR/M10 weeksPrevented or attenuated hypertension by 30 or 10 mg, respectivelyRestoration of NO bioavailability[118]
Aliskiren (10 mg/kg/day) between 2–4 weeks of ageMaternal 50% caloric restrictionSD rat/M12 weeksPrevented hypertensionDecreased renal AGT mRNA; Increased renal ACE2 and MAS receptor protein levels[119]
Aliskiren (10 mg/kg/day) between 2–4 weeks of ageMaternal high-fructose dietSD rat/M and F12 weeksPrevented hypertension in both sexesIncreased renal ACE2 and MAS receptor protein levels in F[52]
ACEI
Captopril (100 mg/kg/day)
between 2–4 weeks of age		Maternal protein restriction Wistar rat/M12 weeksPrevented hypertensionNot evaluated[63]
Captopril (100 mg/kg b.w./day) between 4–10 weeks of ageGenetic hypertension modelSHR/M30 weeksAttenuated hypertensionNot evaluated[147]
Enalapril (100 mg/L) in drinking water between 3–6 weeks of ageMaternal protein restriction SD rat/M16 weeksPrevented hypertensionNot evaluated[148]
Enalapril (100 mg/L) in drinking water between 3–6 weeks of ageMaternal protein restrictionSD rat/M6 monthsPrevented hypertension and albuminuriaReduced urinary AGT and ANG II levels[149]
Perindopril (3 mg/kg/day) between 4–16 weeks of ageGenetic hypertension modelSHR/M28 weeksAttenuated hypertension and renal dysfunctionNot evaluated[150]
ARB
Losartan (100 mg/L) in drinking water between 2–4 weeks of ageMaternal protein restriction Wistar rat/M12 weeksPrevented hypertensionNot evaluated[151]
Losartan (20 mg/kg/day) between 2–4 weeks of ageMaternal 50% caloric restriction SD rat/M12 weeksPrevented hypertensionDecreased renal AGT mRNA[118]
Losartan (20 mg/kg/day) between 4–9 weeks of ageGenetic hypertension modelSHR/M9 weeksPrevented hypertensionIncreased renal ACE2 expression[152]
AT1R antisense
AT1R antisense delivery at 5 days of ageGenetic hypertension modelSHR/M3 monthsPrevented hypertensionDecreased AT1R mRNA[153]
ACE2 activator
Diminazene aceturate in pregnancyMaternal hypertension SHR/M16 weeksAttenuated hypertension and renal fibrosisNot evaluated in the kidney[154]
ANG-(1-7) in pregnancyMaternal hypertensionSHR/M16 weeksAttenuated hypertension and renal fibrosisNot evaluated in the kidney[154]
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Hsu, C.-N.; Tain, Y.-L. Targeting the Renin–Angiotensin–Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins. Int. J. Mol. Sci. 2021, 22, 2298. https://doi.org/10.3390/ijms22052298

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Hsu C-N, Tain Y-L. Targeting the Renin–Angiotensin–Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins. International Journal of Molecular Sciences. 2021; 22(5):2298. https://doi.org/10.3390/ijms22052298

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Hsu, Chien-Ning, and You-Lin Tain. 2021. "Targeting the Renin–Angiotensin–Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins" International Journal of Molecular Sciences 22, no. 5: 2298. https://doi.org/10.3390/ijms22052298

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