Uremic patients on long-term hemodialysis show a paradoxical association of hemorrhages on the one hand and thrombotic complications or atherosclerosis on the other. Platelet function has been found to be depressed in some cases but... more
Uremic patients on long-term hemodialysis show a paradoxical association of hemorrhages on the one hand and thrombotic complications or atherosclerosis on the other. Platelet function has been found to be depressed in some cases but enhanced in others. In 19 patients, both platelet aggregation and prostaglandin formation appeared to be significantly enhanced in response to low concentrations of arachidonic acid but significantly reduced with high concentrations. It is suggested that this double functional abnormality of uremic platelets may contribute to the complex vascular disturbances of hemodialyzed patients.
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More effective treatments for diabetic nephropathy remain a major unmet clinical need. Increased oxidative stress is one of the most important pathological mechanisms that lead to kidney damage and functional impairment induced by... more
More effective treatments for diabetic nephropathy remain a major unmet clinical need. Increased oxidative stress is one of the most important pathological mechanisms that lead to kidney damage and functional impairment induced by diabetes. Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase and critically regulates cellular reactive oxygen species (ROS) production and detoxification. Honokiol is a natural biphenolic compound that, by activating mitochondrial SIRT3, can carry out anti-oxidant, anti-inflammatory and anti-fibrotic activities. Here, we sought to investigate the renoprotective effects of honokiol in BTBR ob/ob mice with type 2 diabetes. Diabetic mice were treated with vehicle or honokiol between the ages of 8 and 14 weeks. Wild-type mice served as controls. Renal Sirt3 expression was significantly reduced in BTBR ob/ob mice, and this was associated with a reduction in its activity and increased ROS levels. Selective activation of SIRT3 through honokiol administratio...
Research Interests: Endocrinology, Oxidative Stress, Medicine, SOD, Diabetic Nephropathy, and 4 moreAlbuminuria, Podocyte, Sirtuin, and SIRT
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MicroRNAs (miRNAs) are important regulators of gene expression, and the dysregulation of miRNAs is a common feature of several diseases. More miRNAs are identified almost daily, revealing the complexity of these transcripts in eukaryotic... more
MicroRNAs (miRNAs) are important regulators of gene expression, and the dysregulation of miRNAs is a common feature of several diseases. More miRNAs are identified almost daily, revealing the complexity of these transcripts in eukaryotic cellular networks. The study of renal miRNAs, using genetically modified mice or by perturbing endogenous miRNA levels, has revealed the important biologic roles miRNAs have in the major cell lineages that compose the glomerulus. Here, we provide an overview of miRNA biogenesis and function in regulating key genes and cellular pathways in glomerular cells during development and homeostasis. Moreover, we focus on the emerging mechanisms through which miRNAs contribute to different diseases affecting the glomerulus, such as FSGS, IgA nephropathy, lupus nephritis, and diabetic nephropathy. In-depth knowledge of miRNA-based gene regulation has made it possible to unravel pathomechanisms, enabling the design of new therapeutic strategies for glomerular d...
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Research Interests: Biology, Scanning Electron Microscopy, Membrane Proteins, Immunohistochemistry, Cell Biology, and 15 moreStem Cell, Medicine, Biological Sciences, Cell Differentiation, Humans, Embryonic Stem Cell, Karyotype, Induced Pluripotent Stem Cells, Synaptophysin, Nephrin, Podocyte, Podocytes, Cadherins, Medical and Health Sciences, and embryoid bodies
The aim of our study was to assess whether the development of chronic uremia in rats with extensive renal mass ablation was associated with an impairment of primary hemostasis as occurs in humans with terminal uremia. We also wanted to... more
The aim of our study was to assess whether the development of chronic uremia in rats with extensive renal mass ablation was associated with an impairment of primary hemostasis as occurs in humans with terminal uremia. We also wanted to assess whether uremic rats had an increased generation of vascular prostacyclin (PGI2) and whether conjugated estrogens could influence such an abnormality. Our results showed that the development of chronic renal failure in rats was associated with a significant prolongation of bleeding time as reported in humans. Thoracic aorta and inferior vena cava specimens from uremic rats produced significantly more 6-keto-prostaglandin F1 alpha (the stable breakdown product of PGI2) than did specimens from the corresponding controls. Conjugated estrogens significantly shortened the bleeding time of uremic rats. The effect on bleeding time was detectable in the majority of animals within 4 hours from conjugated estrogen injection, reached its maximum at 24 hour...
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Background: The incidence of kidney diseases is increasing worldwide and they are emerging as a major public health problem. Once mostly considered inexorable, renal disease progression can now be halted and lesions can even regress with... more
Background: The incidence of kidney diseases is increasing worldwide and they are emerging as a major public health problem. Once mostly considered inexorable, renal disease progression can now be halted and lesions can even regress with drugs such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II type I receptor blockers, indicating the possibility of kidney repair. Summary: The discovery of renal progenitor cells lining the Bowman capsule of adult rat and human kidneys has shed light on the mechanism of repair by ACEi. Parietal progenitors are a reservoir of cells that contribute to podocyte turnover in physiological conditions. In the early phases of renal disease these progenitors migrate chaotically and subsequently proliferate, accumulating in Bowman's space. The abnormal behavior of parietal progenitors is sustained by the activation of CXCR4 receptors in response to an increased production of the chemokine SDF-1 by podocytes activated by the inflammat...
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Research Interests: Endocrinology, Dialysis, Immunohistochemistry, Internal Medicine, Kidney, and 15 moreCapillaries, Animals, Drinking Water, Clinical Sciences, Kidney Disease, Disease Progression, Angiotensin Converting Enzyme, Angiotensin II, Angiotensin Converting Enzyme Inhibitors, Glomerulosclerosis, Creatinine, Lisinopril, Experimental Model, Focal Segmental Glomerulosclerosis, and Kidney glomerulus
Research Interests: Endocrinology, Dialysis, Internal Medicine, Kidney, Blood Pressure, and 15 moreAnimals, Enzyme, Clinical Sciences, Arginine, Combination drug therapy, Disease Progression, Angiotensin Converting Enzyme, Angiotensin Converting Enzyme Inhibitors, ACE Inhibitor, Glomerulonephritis, cyclic GMP, Lisinopril, Combination Therapy, Drug combinations, and biological effect
Research Interests: Endocrinology, Aging, Medicine, Internal Medicine, Kidney, and 15 moreBlood Pressure, Animals, End Stage Renal Failure, Male, Drinking Water, Clinical Sciences, Angiotensin Converting Enzyme, Angiotensin II, Chronic Kidney Failure, Nephrectomy, Long Term Study, ACE Inhibitor, Creatinine, Lisinopril, and Endothelins
Research Interests: Immune response, Kidney diseases, Kidney transplantation, Medicine, Kidney, and 15 moreAnimals, Functional impairment, Renal Function, Enzyme, Clinical Sciences, T lymphocytes, Rats, Kidney Transplant, Renal biopsy, Angiotensin Converting Enzyme Inhibitors, ACE Inhibitor, Recovery of Function, Chronic Allograft Nephropathy, trandolapril, and renal insufficiency
Research Interests: Endocrinology, Dialysis, Internal Medicine, Kidney, Animals, and 15 moreDrinking Water, Clinical Sciences, Group, Kidney Disease, Body Weight, Disease Progression, Angiotensin Converting Enzyme, Angiotensin II, Angiotensin Converting Enzyme Inhibitors, Glomerulosclerosis, ACE Inhibitor, Age Groups, Glomerular Filtration Rate, Combination Therapy, and Antihypertensive agents
ABSTRACT. Renin-angiotensin system (RAS) inhibitors are effective in reducing renal disease progression in early diabetic nephropathy, but they provide imperfect protection at a later stage. Due to the pivotal role of transforming growth... more
ABSTRACT. Renin-angiotensin system (RAS) inhibitors are effective in reducing renal disease progression in early diabetic nephropathy, but they provide imperfect protection at a later stage. Due to the pivotal role of transforming growth factor–β (TGF-β) in the pathogenesis of diabetic kidney disease, this study tested the effect of simultaneously interrupting TGF-β and angiotensin II on disease progression in diabetic rats with overt nephropathy. Diabetes was induced by streptozotocin injection in uninephrectomized rats. Diabetic rats received murine (1D11) or human (CAT-192) anti-TGF-β monoclonal antibodies alone or in combination with lisinopril, 13C4 irrelevant murine antibody, saline or lisinopril from month 4 (when animals had proteinuria) to month 8. Normal animals served as controls. Systolic BP increase was controlled by single treatments and even more by the combined therapies. 1D11 and lisinopril kept proteinuria at levels numerically lower than irrelevant antibody and sa...
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Research Interests: Endocrinology, Nephrology, Immunohistochemistry, Medicine, Probability, and 15 moreInternal Medicine, Mice, Animals, Protein Trafficking, Clinical Sciences, Nephropathy, Genetically Modified, Kidney Disease, Disease Progression, Base Sequence, Angiotensin II, Photomicrography, Angiotensin Converting Enzyme Inhibitors, Calcium Channel Blocker, and Molecular Sequence Data
Research Interests: Microscopy, Biology, Transmission Electron Microscopy, Medicine, Animals, and 15 moreThe, Clinical Sciences, Radius, Rats, Proteinuria, Reference Values, Glomerular Basement Membrane, Photomicrography, Podocytes, Glomerular Filtration Rate, Random Allocation, Cell membrane permeability, Slit, Slit Diaphragm, and Kidney glomerulus
Research Interests: Biology, Medicine, Humans, Kidney, Fibrosis, and 4 moreGene, Clinical Sciences, microRNAs, and Lupus Nephritis
Research Interests: Endocrinology, MicroRNA, Biology, Kidney diseases, Chronic kidney disease, and 15 moreMedicine, Kidney, Animals, Male, Fibrosis, Mechanisms, Clinical Sciences, Nephropathy, microRNAs, Deletion, Disease Progression, Angiotensin Converting Enzyme, Angiotensin Converting Enzyme Inhibitors, In Vitro Techniques, and Kidney glomerulus
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Diabetic nephropathy is associated with cardiovascular morbidity. Angiotensin-converting enzyme (ACE) inhibitors provide imperfect renoprotection in advanced type 2 diabetes, and cardiovascular risk remains elevated. Endothelin (ET)-1 has... more
Diabetic nephropathy is associated with cardiovascular morbidity. Angiotensin-converting enzyme (ACE) inhibitors provide imperfect renoprotection in advanced type 2 diabetes, and cardiovascular risk remains elevated. Endothelin (ET)-1 has a role in renal and cardiac dysfunction in diabetes. Here, we assessed whether combination therapy with an ACE inhibitor and ETAreceptor antagonist provided reno- and cardioprotection in rats with overt type 2 diabetes. Four groups of Zucker diabetic fatty (ZDF) rats were treated orally from 4 (when proteinuric) to 8 mo with vehicle, ramipril (1 mg/kg), sitaxsentan (60 mg/kg), and ramipril plus sitaxsentan. Lean rats served as controls. Combined therapy ameliorated proteinuria and glomerulosclerosis mostly as a result of the action of ramipril. Simultaneous blockade of ANG II and ET-1 pathways normalized renal monocyte chemoattractant protein-1 and interstitial inflammation. Cardiomyocyte loss, volume enlargement, and capillary rarefaction were pro...
Research Interests: Endocrinology, Chemistry, Immunohistochemistry, Medicine, Internal Medicine, and 15 moreEnalapril, Kidney, Blood Glucose, Hemodynamics, Animals, Cardioprotection, Male, Heart, American, Medical Physiology, Body Weight, Angiotensin Converting Enzyme Inhibitors, ACE Inhibitor, Cell count, and Kidney function tests
We previously reported that in a model of spontaneously progressive glomerular injury with early podocyte loss, abnormal migration, and proliferation of glomerular parietal epithelial progenitor cells contributed to the formation of... more
We previously reported that in a model of spontaneously progressive glomerular injury with early podocyte loss, abnormal migration, and proliferation of glomerular parietal epithelial progenitor cells contributed to the formation of synechiae and crescentic lesions. Here we first investigated whether a similar sequence of events could be extended to rats with adriamycin (ADR)-induced nephropathy. As a second aim, the regenerative potential of therapy with bone marrow-derived mesenchymal stem cells (MSCs) on glomerular resident cells was evaluated. In ADR-treated rats, decrease of WT1+podocyte number due to apoptosis was associated with reduced glomerular expression of nephrin and CD2AP. As a consequence of podocyte injury, glomerular adhesions of the capillary tuft to the Bowman's capsule were observed, followed by crescent-like lesions and glomerulosclerosis. Cellular components of synechiae were either NCAM+parietal progenitor cells or nestin+podocytes. In ADR rats, repeated i...
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The capacity of renin-angiotensin system (RAS) inhibitors to delay progression of diabetic nephropathy depends on the time at which therapy is started. A multimodal intervention is required to afford renoprotection in overt diabetic... more
The capacity of renin-angiotensin system (RAS) inhibitors to delay progression of diabetic nephropathy depends on the time at which therapy is started. A multimodal intervention is required to afford renoprotection in overt diabetic nephropathy. Here we assessed the effects of maximal RAS inhibition by angiotensin-converting enzyme (ACE) inhibitor plus angiotensin II type 1 receptor blocker (ARB) in combination with statin in rats with overt diabetic nephropathy. Uninephrectomized rats made diabetic by streptozotocin were orally treated from 4 (when proteinuria and renal lesions had developed) to 8 mo with vehicle, lisinopril plus candesartan, lisinopril plus candesartan plus rosuvastatin, or rosuvastatin alone. Systolic blood pressure increased in diabetic rats and was significantly lowered by combined therapies. Dual RAS blockade significantly reduced proteinuria compared with vehicle. Addition of statin further lowered proteinuria to control levels. Glomerulosclerosis was amelior...
Research Interests: Endocrinology, Immunohistochemistry, Internal Medicine, Kidney, Blood Pressure, and 15 moreCholesterol, Animals, Male, American, Fibrosis, Lipid metabolism, Medical Physiology, Diabetic Nephropathy, Angiotensin Converting Enzyme Inhibitors, Glomerulosclerosis, ACE Inhibitor, Lisinopril, Kidney function tests, Kidney glomerulus, and Diabetic nephropathies
Research Interests: Biology, Membrane Proteins, Immunohistochemistry, Transcription Factors, Medicine, and 15 moreLinear models, Humans, Kidney, Female, Animals, Male, Aged, Middle Aged, Rats, Type 2 Diabetes Mellitus, Angiotensin II, Case Control Studies, real time polymerase chain reaction, Medical and Health Sciences, and Diabetic nephropathies
Research Interests: Stem Cells, Biology, Medicine, Mitosis, Humans, and 15 moreKidney, Animals, Male, Rats, Time Factors, Wistar Rats, Angiotensin Converting Enzyme, Cell Proliferation, Chronic Kidney Failure, Podocyte, Angiotensin Converting Enzyme Inhibitors, Podocytes, Creatinine, Medical and Health Sciences, and Kidney glomerulus
Research Interests: Pathology, Biology, Scanning Electron Microscopy, Membrane Proteins, Immunohistochemistry, and 15 moreMedicine, Pathophysiology, Hypertension, Animals, Male, Rats, Rat Model, Proteinuria, Podocyte, Podocytes, Glomerulosclerosis, The American, reverse transcriptase polymerase chain reaction, Medical and Health Sciences, and Kidney glomerulus
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Generating kidney organoids using human stem cells could offer promising prospects for research and therapeutic purposes. However, no cell-based strategy has generated nephrons displaying an intact three-dimensional epithelial filtering... more
Generating kidney organoids using human stem cells could offer promising prospects for research and therapeutic purposes. However, no cell-based strategy has generated nephrons displaying an intact three-dimensional epithelial filtering barrier. Here, we generated organoids using murine embryonic kidney cells, and documented that these tissues recapitulated the complex three-dimensional filtering structure of glomerular slits in vivo and accomplished selective glomerular filtration and tubular reabsorption. Exploiting this technology, we mixed human amniotic fluid stem cells with mouse embryonic kidney cells to establish three-dimensional chimeric organoids that engrafted in vivo and grew to form vascularized glomeruli and tubular structures. Human cells contributed to the formation of glomerular structures, differentiated into podocytes with slit diaphragms, and internalized exogenously infused BSA, thus attaining in vivo degrees of specialization and function unprecedented for don...
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Chronic renal insufficiency inexorably progresses in patients, such as it does after partial renal ablation in rats. However, the progression of renal diseases can be delayed by angiotensin II blockers that stabilize renal function or... more
Chronic renal insufficiency inexorably progresses in patients, such as it does after partial renal ablation in rats. However, the progression of renal diseases can be delayed by angiotensin II blockers that stabilize renal function or increase GFR, even in advanced phases of the disease. Regression of glomerulosclerosis can be induced by angiotensin II antagonism, but the effect of these treatments on the entire vascular tree is unclear. Here, using microcomputed tomography and scanning electron microscopy, we compared the size and extension of kidney blood vessels in untreated Wistar rats with those in untreated and angiotensin II antagonist-treated Munich Wistar Frömter (MWF) rats that spontaneously develop kidney disease with age. The kidney vasculature underwent progressive rarefaction in untreated MWF rats, substantially affecting intermediate and small vessels. Microarray analysis showed increased Tgf-β and endothelin-1 gene expression with age. Notably, 10-week inhibition of ...
Research Interests: Endocrinology, Scanning Electron Microscopy, Apoptosis, Medicine, Gene expression, and 15 moreInternal Medicine, Kidney, Capillaries, Endothelial Cells, Renin Angiotensin Aldosterone System, Animals, Clinical Sciences, Rats, Kidney Disease, Cell Proliferation, Angiotensin II, Angiotensin Converting Enzyme Inhibitors, Endothelin Receptor, Kidney glomerulus, and Angiotensin Receptor Antagonists
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Research Interests: Endocrinology, Medicine, Internal Medicine, Kidney, Blood Pressure, and 15 moreAnimals, Male, Drinking Water, Clinical Sciences, Membranous Nephropathy, Rats, Angiotensin Converting Enzyme, Proteinuria, Angiotensin II, Renal disease, ACE Inhibitor, Creatinine, Glomerulonephritis, Endothelin Receptor, and Combination Therapy
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Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the leading cause of end-stage kidney disease. Both diabetes and chronic kidney disease are risk factors for cardiovascular disease, and... more
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the leading cause of end-stage kidney disease. Both diabetes and chronic kidney disease are risk factors for cardiovascular disease, and diabetic patients with renal involvement are three times more likely to eventually die of cardiovascular disease than diabetic patients without signs of renal failure. In type 2 diabetes, microalbuminuria is a marker of renal dysfunction and a crucial predictor of cardiovascular disease. Inhibitors of angiotensin II synthesis/activity, while preventing micro- or macroalbuminuria, also reduced cardiovascular events in diabetic patients. However, the effectiveness of renin angiotensin system blocking agents depends on the time when treatment is started, and imperfect renoprotection may occur if therapy begins at an advanced disease phase. This raises the need to identify novel multidrug approaches that simultaneously inhibit additional pathways other th...
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Research Interests: Endocrinology, Chemistry, Medicine, In Situ Hybridization, Internal Medicine, and 15 moreAnimals, Male, Enzyme, Clinical Sciences, Angiotensin Converting Enzyme, Imidazoles, Base Sequence, Angiotensin II, Glomerular Basement Membrane, Angiotensin Converting Enzyme Inhibitors, ACE Inhibitor, Glomerulonephritis, Lisinopril, Kidney glomerulus, and Angiotensin Receptor Antagonists
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Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most common causes of nephrotic syndrome in children and in young adults. Relapsing MCD carries the risk of severe complications and prolonged... more
Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most common causes of nephrotic syndrome in children and in young adults. Relapsing MCD carries the risk of severe complications and prolonged immunosuppression, while FSGS remains largely untreatable and urgently needs more effective treatments. Recently, induction of B7-1 (CD80), an immune-related protein expressed by antigen-presenting cells, was observed in podocytes of MCD and FSGS patients, suggesting that B7-1 plays a role in the pathogenesis of these diseases, and hence that abatacept, a B7-1 inhibitor, could be a possible treatment. Since previous studies raised serious concerns regarding the reliability of immunohistochemical assays for B7-1 detection and the efficacy of B7-1 inhibitory treatment, we investigated B7-1 podocyte expression in MCD and FSGS patients. Using different primary antibodies and immunohistochemical assays, no significant up-regulation of podocyte B7-1 was detected in p...
Research Interests: Physiology, Biomarkers, Immunohistochemistry, Medicine, Humans, and 15 moreFemale, Animals, Male, Immunosuppression, Medical Physiology, Membranous Nephropathy, Aged, Middle Aged, Doxorubicin, Adult, Podocyte, Glomerulosclerosis, Nephrotic syndrome, Case Control Studies, and Focal Segmental Glomerulosclerosis
The incidence of progressive kidney disease associated with diabetes continues to rise worldwide. Current standard therapy with angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers achieves only partial... more
The incidence of progressive kidney disease associated with diabetes continues to rise worldwide. Current standard therapy with angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers achieves only partial renoprotection, increasing the need for novel therapeutic approaches. Previous studies described B7-1 induction in podocytes of patients with proteinuria, including those with FSGS and type 2 diabetic nephropathy (DN). These findings sparked great excitement in the renal community, implying that abatacept, a costimulatory inhibitor that targets B7-1, could be a novel therapy for diabetic renal disease. Given previous concerns over the value of B7-1 immunostaining and the efficacy of abatacept in patients with recurrent FSGS after renal transplantation, we investigated B7-1 expression in human and experimental DN before embarking on clinical studies of the use of B7-1 targeting strategies to treat proteinuria in DN. Immunohistochemical analysis of kidney speci...