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 (VEGFKD ) 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 VEGFKD led to diffuse glomerulosclerosis, foot process effacement, and GBM thickening in both diabetic mice with intact eNOS and in non-diabetic eNOS−/−:VEGFKD mice. VEGFKD diabetic mice developed mild proteinuria and maintained normal glomerular filtration rate (GFR), associated with extremely high NO and thiol urinary excretion. In eNOS−/−:VEGFKD (+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 VEGFKD diabetic mice with intact eNOS, whereas VEGFKD induction in eNOS−/−:VEGFKD mice causes massive proteinuria and renal failure mimicking DKD in the absence of diabetes. Mechanistically, we identify VEGFKD -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.
Highlights
Diabetic kidney disease (DKD) is a major complication of both type 1 and type 2 diabetes that leads to renal failure, and the single most frequent cause of end-stage renal disease (ESRD) worldwide (Tuttle et al, 2014)
We have shown that podocyte Vascular endothelial growth factor-a (VEGF-A) gain-of-function in diabetic mice leads to the development of Kimmelstiel-Wilson-like nodular glomerulosclerosis and massive proteinuria (Veron et al, 2011)
This study demonstrates that in the setting of bioavailable nitric oxide (NO) deficiency, caused by diabetic milieu or by eNOS knockout, podocyte VEGF-A knockdown results in diffuse glomerulosclerosis and proteinuria of increasing severity, leading to renal failure in eNOS−/−:VEGFKD mice
Summary
Diabetic kidney disease (DKD) is a major complication of both type 1 and type 2 diabetes that leads to renal failure, and the single most frequent cause of end-stage renal disease (ESRD) worldwide (Tuttle et al, 2014). We have shown that podocyte VEGF-A gain-of-function in diabetic mice leads to the development of Kimmelstiel-Wilson-like nodular glomerulosclerosis and massive proteinuria (Veron et al, 2011). We showed that VEGF-A gain-of-function in eNOS KO mice induces nodular glomerulosclerosis, massive proteinuria and renal failure in the absence of diabetes (Veron et al, 2014). These findings demonstrated that NO deficiency and excess VEGF-A have a synergistic deleterious effect that is necessary and sufficient for the development of nodular glomerulosclerosis, the prototypical glomerular phenotype of human advanced DKD (Veron et al, 2014). Short term VEGF-A knockdown in podocytes induces acute renal failure and proteinuria associated with endotheliosis, mesangiolysis, and microaneurisms (Veron et al, 2012), and VEGF-A deletion accelerates DKD in a short term diabetes mouse model (Sivaskandarajah et al, 2012)
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