Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice.
ABSTRACT For investigation of how the vascular endothelial growth factor (VEGF) system participates in the pathogenesis of diabetic kidney disease, type 2 diabetic db/db and control db/m mice were treated intraperitoneally with vehicle or 2 mg/kg of a pan-VEGF receptor tyrosine kinase inhibitor, SU5416, twice a week for 8 wk. Efficacy of SU5416 treatment in the kidney was verified by the inhibition of VEGF receptor-1 phosphorylation. Glomerular VEGF immunostaining, normally increased in diabetes, was unaffected by SU5416. Plasma creatinine did not change with diabetes or SU5416 treatment. The primary end point of albuminuria increased approximately four-fold in the diabetic db/db mice but was significantly ameliorated by SU5416. Correlates of albuminuria were investigated. Diabetic glomerular basement membrane thickening was prevented in the SU5416-treated db/db mice, whereas mesangial matrix expansion remained unchanged by treatment. The density of open slit pores between podocyte foot processes was decreased in db/db diabetes but was partly increased toward normal by SU5416. Finally, nephrin protein by immunofluorescence was decreased in the db/db mice but was significantly restored by SU5416. Paradoxically, total nephrin protein by immunoblotting was increased in diabetes, pointing toward a possible dysregulation of nephrin trafficking. Diabetic albuminuria is partially a function of VEGF receptor signaling overactivity. VEGF signaling was found to affect a number of podocyte-driven manifestations such as GBM thickening, slit pore density, and nephrin quantity, all of which are associated with the extent of diabetic albuminuria. By impeding these pathophysiologic processes, VEGF receptor inhibition by SU5416 might become a useful adjunct to anti-albuminuria therapy in diabetic nephropathy.
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ABSTRACT: Vascular endothelial growth factor-A (VEGF-A) is a protein secreted by podocytes that is necessary for survival of endothelial cells, podocytes, and mesangial cells. VEGF-A regulates slit-diaphragm signaling and podocyte shape via VEGF-receptor 2-nephrin-nck-actin interactions. Chronic hyperglycemia-induced excess podocyte VEGF-A and low endothelial nitric oxide drive the development and the progression of diabetic nephropathy. The abnormal cross-talk between VEGF-A and nitric oxide pathways is fueled by the diabetic milieu, resulting in increased oxidative stress. Recent findings on these pathogenic molecular mechanisms provide new potential targets for therapy for diabetic renal disease.Seminars in Nephrology 07/2012; 32(4):385-93. · 2.12 Impact Factor
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ABSTRACT: Diabetes is the leading cause of chronic kidney disease, which in the Thailand is the most common cause of end stage renal disease (ESRD) requiring dialysis. Patients with diabetic kidney disease (DKD) are at a higher risk of mortality, mostly from cardiovascular complications, than other patients with diabetes. The development of DKD is determined by environmental and genetic factors. This review focuses on the latest published data dealing with mechanisms and treatment of DKD. DKD has several distinct phases of development of the disease and hyperglycemia-induced metabolic and hemodynamic pathways are recognized to be mediators of kidney disease. Multiple biochemical pathways have been postulated that explain how hyperglycemia causes tissue damage: nonenzymatic glycosylation that generates advanced glycosylation end products, activation of protein kinase C, and acceleration of the polyol pathway. Oxidative stress also seems to be a theme common pathway. These derangements, along with hemodynamic changes, activate various cytokines and growth factors such as vascular endothelial growth factor, transforming growth factor-beta2 Interleukin 1 (IL 1), IL-6 and IL-18. Current renoprotective treatments for DKD include optimization of glycemic, blood pressure, lipid and weight control blockade of the renin-angiotensin system, salt and protein restriction. Multiple intensive interventions reduce cardiovascular events as well as nephropathy by about half when compared with a conventional multifactorial treatment.Journal of the Medical Association of Thailand = Chotmaihet thangphaet 11/2010; 93 Suppl 6:S228-41.
Article: Podocyte vascular endothelial growth factor (Vegf₁₆₄) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes.[show abstract] [hide abstract]
ABSTRACT: The pathogenic role of excessive vascular endothelial growth factor (VEGF)-A in diabetic nephropathy has not been defined. We sought to test whether increased podocyte VEGF-A signalling determines the severity of diabetic glomerulopathy. Podocyte-specific, doxycycline-inducible Vegf₁₆₄ (the most abundant Vegfa isoform) overexpressing adult transgenic mice were made diabetic with low doses of streptozotocin and examined 12 weeks after onset of diabetes. We studied diabetic and non-diabetic transgenic mice fed a standard or doxycycline-containing diet. VEGF-A and albuminuria were measured by ELISA, creatinine was measured by HPLC, renal morphology was examined by light and electron microscopy, and gene expression was assessed by quantitative PCR, immunoblotting and immunohistochemistry. Podocyte Vegf₁₆₄ overexpression in our mouse model of diabetes resulted in advanced diabetic glomerulopathy, characterised by Kimmelstiel-Wilson-like nodular glomerulosclerosis, microaneurysms, mesangiolysis, glomerular basement membrane thickening, podocyte effacement and massive proteinuria associated with hyperfiltration. It also led to increased VEGF receptor 2 and semaphorin3a levels, as well as nephrin and matrix metalloproteinase-2 downregulation, whereas circulating VEGF-A levels were similar to those in control diabetic mice. Collectively, these data demonstrate that increased podocyte Vegf₁₆₄ signalling dramatically worsens diabetic nephropathy in a streptozotocin-induced mouse model of diabetes, resulting in nodular glomerulosclerosis and massive proteinuria. This suggests that local rather than systemic VEGF-A levels determine the severity of diabetic nephropathy and that semaphorin3a signalling and matrix metalloproteinase-2 dysregulation are mechanistically involved in severe diabetic glomerulopathy.Diabetologia 02/2011; 54(5):1227-41. · 6.81 Impact Factor