Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally descr... more Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally described as a key process for organ development and metastasis budding in cancer, plays a key role in the development of renal fibrosis in several diseases, including hypertensive nephroangiosclerosis. We herein reviewed the concept of EMT and its role in renal diseases, with particular focus on hypertensive kidney disease, the second leading cause of end-stage renal disease after diabetes mellitus. After discussing the pathophysiology of hypertensive nephropathy, the ‘classic’ view of hypertensive nephrosclerosis entailing hyalinization, and sclerosis of interlobular and afferent arterioles, we examined the changes occurring in the glomerulus and tubulo-interstitium and the studies that investigated the role of EMT and its molecular mechanisms in hypertensive kidney disease. Finally, we examined the reasons why some studies failed to provide solid evidence for renal EMT in hypertension.
Background. The mutations that affect the selectivity filter of the KCNJ5 K+ channel can play a r... more Background. The mutations that affect the selectivity filter of the KCNJ5 K+ channel can play a role in triggering and/or maintaining aldosterone oversecretion in primary aldosteronism (PA). We therefore hypothesized that these somatic mutations can be associated with an increased aldosterone secretion from the APA, thus translating in raised plasma aldosterone concentrations (PAC) in the ipsilateral adrenal vein. Aim. To investigate if the lateralization index (LI) at adrenal vein sampling (AVS) is higher in the patients with an APA carrying the mutation (KCNJ5mut), as compared to those without the mutation (KCNJ5wt). Methods. Ninety-two consecutive PA patients who underwent AVS and received diagnosis of APA based on the four corners criteria were recruited. Unequivocal information on the presence or absence of the KCNJ5 mutations was available for each patient. The selectivity index (SI) was calculated as ratio between the right or left adrenal vein PCC (PCCside) and the infrarenal IVC PCC and a cutoff of 2.00 was used. The lateralization index (LI) was calculated in the bilaterally selective AVS as the ratio of PAC/PCC at the APA side to PAC/PCC at the contralateral side. We sequenced the KCNJ5 coding region spanning aminoacids 122 to 199, which include the selectivity filer. Results. The overall prevalence rate of KCNJ5 somatic mutations was 34%; G151R, L168R and T158A mutations were found in 19, 10 and 1 APA respectively. The G151E mutation was not found. The KCNJ5mut and KCNJ5wt groups were similar for gender, age, sK+ levels, while PAC and ARR were higher, and PRA lower (all p<0.05) in the KCNJ5 mut group. In the latter group the LI was higher than in the KCNJ5wt group (29.3± 6.7 vs 16.7±3.9, p< 0.02). This was due to a PAC/PCC ratio which was higher in the adrenal vein ipsilateral to the APA side and lower contralaterally in the KCNJ5mut group. Conclusions. These results provide direct in vivo evidence for a higher aldosterone secretion from APA carrying the KCNJ5 mutations, which translates into higher values of the LI, compared to the tumors without such mutations. Hence, the presence of these KCNJ5 mutations can affect the accuracy of the AVS-based diagnosis of the subtype of PA.
We tested the hypothesis that tubulo-interstitial fibrosis (TIF), the final outcome of most kidne... more We tested the hypothesis that tubulo-interstitial fibrosis (TIF), the final outcome of most kidney diseases, involves activation of epithelial mesenchymal transition (EMT) through angiotensin II- and endothelin-1 (ET-1)-mechanisms. In a transgenic model of fulminant angiotensin II-dependent hypertension with early prominent renal damage, the TG(mRen2)27 rat (TGRen2), we found that the development of renal damage implied a decrease of the epithelial marker E-cadherin and an increase of the mesenchymal markers alpha SMA and vimentin, which indicated the occurrence of EMT. As treatment with the angiotensin II type 1 receptor antagonist irbesartan, or with the mixed ET-1 receptor antagonist bosentan, prevented these changes an involvement of both angiotensin II and ET-1 in EMT is suggested. To confirm this contention we exposed HK-2 human kidney tubular cells to ET-1. This showed that ET-1 blunted the expression of E-cadherin, increased that of alpha SMA and vimentin, enhanced the synthesis of collagen, and also the activity of metalloproteinases (MMP). These changes implicated activation of Rho-kinase signaling pathway and de-phosphorylation of Yes-associated protein (YAP). Hence, ex vivo and in vitro experiments demonstrated that EMT is a fundamental process in the TIF that accompanies the development of angiotensin II-dependent hypertension. Moreover, they suggested that EMT involves ET-1 acting via ETA and ETB receptors through activation of Rho-kinase and de-activation of YAP pathways.
The large environmental contamination of drinking water by perfluoroalkyl substances (PFAS) marke... more The large environmental contamination of drinking water by perfluoroalkyl substances (PFAS) markedly increased the plasma levels of pentadecafluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in a Northern Italy population with a high prevalence of arterial hypertension and cardiovascular disease. As the link between PFAS and arterial hypertension is unknown, we investigated if they enhance the biosynthesis of the well-known pressor hormone aldosterone. We found that PFAS increased aldosterone synthase (CYP11B2) gene expression by three-fold and doubled aldosterone secretion and cell and mitochondria reactive oxygen species (ROS) production over controls (p < 0.01 for all) in human adrenocortical carcinoma cells HAC15. They also enhanced the effects of Ang II on CYP11B2 mRNA and aldosterone secretion (p < 0.01 for all). Moreover, when added 1 h before, the ROS scavenger tempol abolished the effect of PFAS on CYP11B2 gene expression. These results indicate that ...
Autonomous aldosterone overproduction represents the underlying condition of 5–10% of patients wi... more Autonomous aldosterone overproduction represents the underlying condition of 5–10% of patients with arterial hypertension and carries a significant burden of mortality and morbidity. The diagnostic algorithm for primary aldosteronism is sequentially based on hormonal tests (screening and confirmation tests), followed by lateralization studies (adrenal CT scanning and adrenal venous sampling) to distinguish between unilateral and bilateral disease. Despite the recommendations of the Endocrine Society guideline, primary aldosteronism is largely underdiagnosed and undertreated with high between-centre heterogeneity. Experts from the European Society of Hypertension have critically reviewed the available literature and prepared a consensus document constituting two articles to summarize current knowledge on the epidemiology, diagnosis, treatment, and complications of primary aldosteronism.
The Journal of Clinical Endocrinology & Metabolism, 2019
Context The G protein–coupled estrogen receptor (GPER) mediates an aldosterone secretagogue effec... more Context The G protein–coupled estrogen receptor (GPER) mediates an aldosterone secretagogue effect of 17β-estradiol in human HAC15 adrenocortical cells after estrogen receptor β blockade. Because GPER mediates mineralocorticoid receptor-independent aldosterone effects in other cell types, we hypothesized that aldosterone could modulate its own synthesis via GPER activation. Methods HAC15 cells were exposed to aldosterone in the presence or absence of canrenone, a mineralocorticoid receptor antagonist, and/or of the selective GPER antagonist G36. Aldosterone synthase (CYP11B2) mRNA and protein levels changes were the study end points. Similar experiments were repeated in strips obtained ex vivo from aldosterone-producing adenoma (APA) and in GPER-silenced HAC15 cells. Results Aldosterone markedly increased CYP11B2 mRNA and protein expression (vs untreated samples, P < 0.001) in both models by acting via GPER, because these effects were abolished by G36 (P < 0.01) and not by can...
The Journal of Clinical Endocrinology & Metabolism, 2019
Context Accumulating evidence suggests a link between adrenocortical zona glomerulosa and parathy... more Context Accumulating evidence suggests a link between adrenocortical zona glomerulosa and parathyroid gland through mechanisms that remain unexplored. Objectives To test the hypothesis that in vivo angiotensin II blockade affects PTH secretion in patients with hypertension and that aldosterone and angiotensim II directly stimulate PTH secretion ex vivo. Design and Setting We investigated the changes of serum PTH levels induced by oral captopril (50 mg) administration in patients with primary essential hypertension (EH) and with primary aldosteronism (PA) caused by bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA), the latter before and after adrenalectomy. We also exposed primary cultures of human parathyroid cells from patients with primary hyperparathyroidism to angiotensin II (10−7 M) and/or aldosterone (10−7 M). Results Captopril lowered PTH levels (in nanograms per liter) both in patients with EH (n = 63; 25.9 ± 8.3 baseline vs 24.4 ± 8.0 postcaptopril,...
Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally descr... more Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally described as a key process for organ development and metastasis budding in cancer, plays a key role in the development of renal fibrosis in several diseases, including hypertensive nephroangiosclerosis. We herein reviewed the concept of EMT and its role in renal diseases, with particular focus on hypertensive kidney disease, the second leading cause of end-stage renal disease after diabetes mellitus. After discussing the pathophysiology of hypertensive nephropathy, the ‘classic’ view of hypertensive nephrosclerosis entailing hyalinization, and sclerosis of interlobular and afferent arterioles, we examined the changes occurring in the glomerulus and tubulo-interstitium and the studies that investigated the role of EMT and its molecular mechanisms in hypertensive kidney disease. Finally, we examined the reasons why some studies failed to provide solid evidence for renal EMT in hypertension.
Background. The mutations that affect the selectivity filter of the KCNJ5 K+ channel can play a r... more Background. The mutations that affect the selectivity filter of the KCNJ5 K+ channel can play a role in triggering and/or maintaining aldosterone oversecretion in primary aldosteronism (PA). We therefore hypothesized that these somatic mutations can be associated with an increased aldosterone secretion from the APA, thus translating in raised plasma aldosterone concentrations (PAC) in the ipsilateral adrenal vein. Aim. To investigate if the lateralization index (LI) at adrenal vein sampling (AVS) is higher in the patients with an APA carrying the mutation (KCNJ5mut), as compared to those without the mutation (KCNJ5wt). Methods. Ninety-two consecutive PA patients who underwent AVS and received diagnosis of APA based on the four corners criteria were recruited. Unequivocal information on the presence or absence of the KCNJ5 mutations was available for each patient. The selectivity index (SI) was calculated as ratio between the right or left adrenal vein PCC (PCCside) and the infrarenal IVC PCC and a cutoff of 2.00 was used. The lateralization index (LI) was calculated in the bilaterally selective AVS as the ratio of PAC/PCC at the APA side to PAC/PCC at the contralateral side. We sequenced the KCNJ5 coding region spanning aminoacids 122 to 199, which include the selectivity filer. Results. The overall prevalence rate of KCNJ5 somatic mutations was 34%; G151R, L168R and T158A mutations were found in 19, 10 and 1 APA respectively. The G151E mutation was not found. The KCNJ5mut and KCNJ5wt groups were similar for gender, age, sK+ levels, while PAC and ARR were higher, and PRA lower (all p&amp;amp;lt;0.05) in the KCNJ5 mut group. In the latter group the LI was higher than in the KCNJ5wt group (29.3± 6.7 vs 16.7±3.9, p&amp;amp;lt; 0.02). This was due to a PAC/PCC ratio which was higher in the adrenal vein ipsilateral to the APA side and lower contralaterally in the KCNJ5mut group. Conclusions. These results provide direct in vivo evidence for a higher aldosterone secretion from APA carrying the KCNJ5 mutations, which translates into higher values of the LI, compared to the tumors without such mutations. Hence, the presence of these KCNJ5 mutations can affect the accuracy of the AVS-based diagnosis of the subtype of PA.
We tested the hypothesis that tubulo-interstitial fibrosis (TIF), the final outcome of most kidne... more We tested the hypothesis that tubulo-interstitial fibrosis (TIF), the final outcome of most kidney diseases, involves activation of epithelial mesenchymal transition (EMT) through angiotensin II- and endothelin-1 (ET-1)-mechanisms. In a transgenic model of fulminant angiotensin II-dependent hypertension with early prominent renal damage, the TG(mRen2)27 rat (TGRen2), we found that the development of renal damage implied a decrease of the epithelial marker E-cadherin and an increase of the mesenchymal markers alpha SMA and vimentin, which indicated the occurrence of EMT. As treatment with the angiotensin II type 1 receptor antagonist irbesartan, or with the mixed ET-1 receptor antagonist bosentan, prevented these changes an involvement of both angiotensin II and ET-1 in EMT is suggested. To confirm this contention we exposed HK-2 human kidney tubular cells to ET-1. This showed that ET-1 blunted the expression of E-cadherin, increased that of alpha SMA and vimentin, enhanced the synthesis of collagen, and also the activity of metalloproteinases (MMP). These changes implicated activation of Rho-kinase signaling pathway and de-phosphorylation of Yes-associated protein (YAP). Hence, ex vivo and in vitro experiments demonstrated that EMT is a fundamental process in the TIF that accompanies the development of angiotensin II-dependent hypertension. Moreover, they suggested that EMT involves ET-1 acting via ETA and ETB receptors through activation of Rho-kinase and de-activation of YAP pathways.
The large environmental contamination of drinking water by perfluoroalkyl substances (PFAS) marke... more The large environmental contamination of drinking water by perfluoroalkyl substances (PFAS) markedly increased the plasma levels of pentadecafluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) in a Northern Italy population with a high prevalence of arterial hypertension and cardiovascular disease. As the link between PFAS and arterial hypertension is unknown, we investigated if they enhance the biosynthesis of the well-known pressor hormone aldosterone. We found that PFAS increased aldosterone synthase (CYP11B2) gene expression by three-fold and doubled aldosterone secretion and cell and mitochondria reactive oxygen species (ROS) production over controls (p < 0.01 for all) in human adrenocortical carcinoma cells HAC15. They also enhanced the effects of Ang II on CYP11B2 mRNA and aldosterone secretion (p < 0.01 for all). Moreover, when added 1 h before, the ROS scavenger tempol abolished the effect of PFAS on CYP11B2 gene expression. These results indicate that ...
Autonomous aldosterone overproduction represents the underlying condition of 5–10% of patients wi... more Autonomous aldosterone overproduction represents the underlying condition of 5–10% of patients with arterial hypertension and carries a significant burden of mortality and morbidity. The diagnostic algorithm for primary aldosteronism is sequentially based on hormonal tests (screening and confirmation tests), followed by lateralization studies (adrenal CT scanning and adrenal venous sampling) to distinguish between unilateral and bilateral disease. Despite the recommendations of the Endocrine Society guideline, primary aldosteronism is largely underdiagnosed and undertreated with high between-centre heterogeneity. Experts from the European Society of Hypertension have critically reviewed the available literature and prepared a consensus document constituting two articles to summarize current knowledge on the epidemiology, diagnosis, treatment, and complications of primary aldosteronism.
The Journal of Clinical Endocrinology & Metabolism, 2019
Context The G protein–coupled estrogen receptor (GPER) mediates an aldosterone secretagogue effec... more Context The G protein–coupled estrogen receptor (GPER) mediates an aldosterone secretagogue effect of 17β-estradiol in human HAC15 adrenocortical cells after estrogen receptor β blockade. Because GPER mediates mineralocorticoid receptor-independent aldosterone effects in other cell types, we hypothesized that aldosterone could modulate its own synthesis via GPER activation. Methods HAC15 cells were exposed to aldosterone in the presence or absence of canrenone, a mineralocorticoid receptor antagonist, and/or of the selective GPER antagonist G36. Aldosterone synthase (CYP11B2) mRNA and protein levels changes were the study end points. Similar experiments were repeated in strips obtained ex vivo from aldosterone-producing adenoma (APA) and in GPER-silenced HAC15 cells. Results Aldosterone markedly increased CYP11B2 mRNA and protein expression (vs untreated samples, P < 0.001) in both models by acting via GPER, because these effects were abolished by G36 (P < 0.01) and not by can...
The Journal of Clinical Endocrinology & Metabolism, 2019
Context Accumulating evidence suggests a link between adrenocortical zona glomerulosa and parathy... more Context Accumulating evidence suggests a link between adrenocortical zona glomerulosa and parathyroid gland through mechanisms that remain unexplored. Objectives To test the hypothesis that in vivo angiotensin II blockade affects PTH secretion in patients with hypertension and that aldosterone and angiotensim II directly stimulate PTH secretion ex vivo. Design and Setting We investigated the changes of serum PTH levels induced by oral captopril (50 mg) administration in patients with primary essential hypertension (EH) and with primary aldosteronism (PA) caused by bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA), the latter before and after adrenalectomy. We also exposed primary cultures of human parathyroid cells from patients with primary hyperparathyroidism to angiotensin II (10−7 M) and/or aldosterone (10−7 M). Results Captopril lowered PTH levels (in nanograms per liter) both in patients with EH (n = 63; 25.9 ± 8.3 baseline vs 24.4 ± 8.0 postcaptopril,...
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Papers by Teresa M Seccia