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Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice

Vascular endothelial growth factor-a (VEGF-A) and nitric oxide (NO) are essential for glomerular filtration barrier homeostasis, and are dysregulated in diabetic kidney disease (DKD). While NO availability is consistently low in diabetes, both high and low VEGF-A have been reported in patients with...

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Autores principales: Veron, Delma, Aggarwal, Pardeep K., Li, Qi, Moeckel, Gilbert, Kashgarian, Michael, Tufro, Alda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8906751/
https://www.ncbi.nlm.nih.gov/pubmed/35280251
http://dx.doi.org/10.3389/fphar.2021.788886
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author Veron, Delma
Aggarwal, Pardeep K.
Li, Qi
Moeckel, Gilbert
Kashgarian, Michael
Tufro, Alda
author_facet Veron, Delma
Aggarwal, Pardeep K.
Li, Qi
Moeckel, Gilbert
Kashgarian, Michael
Tufro, Alda
author_sort Veron, Delma
collection PubMed
description Vascular endothelial growth factor-a (VEGF-A) and nitric oxide (NO) are essential for glomerular filtration barrier homeostasis, and are dysregulated in diabetic kidney disease (DKD). While NO availability is consistently low in diabetes, both high and low VEGF-A have been reported in patients with DKD. Here we examined the effect of inducible podocyte VEGF-A knockdown (VEGF(KD) ) in diabetic mice and in endothelial nitric oxide synthase knockout mice (eNOS(−/−) ). Diabetes was induced with streptozotocin using the Animal Models of Diabetic Complications Consortium (AMDCC) protocol. Induction of podocyte VEGF(KD) led to diffuse glomerulosclerosis, foot process effacement, and GBM thickening in both diabetic mice with intact eNOS and in non-diabetic eNOS(−/−):VEGF(KD) mice. VEGF(KD) diabetic mice developed mild proteinuria and maintained normal glomerular filtration rate (GFR), associated with extremely high NO and thiol urinary excretion. In eNOS(−/−):VEGF(KD) (+dox) mice severe diffuse glomerulosclerosis was associated with microaneurisms, arteriolar hyalinosis, massive proteinuria, and renal failure. Collectively, data indicate that combined podocyte VEGF-A and eNOS deficiency result in diffuse glomerulosclerosis in mice; compensatory NO and thiol generation prevents severe proteinuria and GFR loss in VEGF(KD) diabetic mice with intact eNOS, whereas VEGF(KD) induction in eNOS(−/−):VEGF(KD) mice causes massive proteinuria and renal failure mimicking DKD in the absence of diabetes. Mechanistically, we identify VEGF(KD) -induced abnormal S-nitrosylation of specific proteins, including β3-integrin, laminin, and S-nitrosoglutathione reductase (GSNOR), as targetable molecular mechanisms involved in the development of advanced diffuse glomerulosclerosis and renal failure.
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spelling pubmed-89067512022-03-10 Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice Veron, Delma Aggarwal, Pardeep K. Li, Qi Moeckel, Gilbert Kashgarian, Michael Tufro, Alda Front Pharmacol Pharmacology Vascular endothelial growth factor-a (VEGF-A) and nitric oxide (NO) are essential for glomerular filtration barrier homeostasis, and are dysregulated in diabetic kidney disease (DKD). While NO availability is consistently low in diabetes, both high and low VEGF-A have been reported in patients with DKD. Here we examined the effect of inducible podocyte VEGF-A knockdown (VEGF(KD) ) in diabetic mice and in endothelial nitric oxide synthase knockout mice (eNOS(−/−) ). Diabetes was induced with streptozotocin using the Animal Models of Diabetic Complications Consortium (AMDCC) protocol. Induction of podocyte VEGF(KD) led to diffuse glomerulosclerosis, foot process effacement, and GBM thickening in both diabetic mice with intact eNOS and in non-diabetic eNOS(−/−):VEGF(KD) mice. VEGF(KD) diabetic mice developed mild proteinuria and maintained normal glomerular filtration rate (GFR), associated with extremely high NO and thiol urinary excretion. In eNOS(−/−):VEGF(KD) (+dox) mice severe diffuse glomerulosclerosis was associated with microaneurisms, arteriolar hyalinosis, massive proteinuria, and renal failure. Collectively, data indicate that combined podocyte VEGF-A and eNOS deficiency result in diffuse glomerulosclerosis in mice; compensatory NO and thiol generation prevents severe proteinuria and GFR loss in VEGF(KD) diabetic mice with intact eNOS, whereas VEGF(KD) induction in eNOS(−/−):VEGF(KD) mice causes massive proteinuria and renal failure mimicking DKD in the absence of diabetes. Mechanistically, we identify VEGF(KD) -induced abnormal S-nitrosylation of specific proteins, including β3-integrin, laminin, and S-nitrosoglutathione reductase (GSNOR), as targetable molecular mechanisms involved in the development of advanced diffuse glomerulosclerosis and renal failure. Frontiers Media S.A. 2022-02-23 /pmc/articles/PMC8906751/ /pubmed/35280251 http://dx.doi.org/10.3389/fphar.2021.788886 Text en Copyright © 2022 Veron, Aggarwal, Li, Moeckel, Kashgarian and Tufro. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Veron, Delma
Aggarwal, Pardeep K.
Li, Qi
Moeckel, Gilbert
Kashgarian, Michael
Tufro, Alda
Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice
title Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice
title_full Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice
title_fullStr Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice
title_full_unstemmed Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice
title_short Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice
title_sort podocyte vegf-a knockdown induces diffuse glomerulosclerosis in diabetic and in enos knockout mice
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8906751/
https://www.ncbi.nlm.nih.gov/pubmed/35280251
http://dx.doi.org/10.3389/fphar.2021.788886
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