AUTHOR=Veron Delma , Aggarwal Pardeep K. , Li Qi , Moeckel Gilbert , Kashgarian Michael , Tufro Alda TITLE=Podocyte VEGF-A Knockdown Induces Diffuse Glomerulosclerosis in Diabetic and in eNOS Knockout Mice JOURNAL=Frontiers in Pharmacology VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.788886 DOI=10.3389/fphar.2021.788886 ISSN=1663-9812 ABSTRACT=

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.