VEGF and Podocytes in Diabetic Nephropathy

Abstract

Summary 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 VEGFR2-nephrin-nck-actin interactions. Chronic hyperglycemia-induced excess podocyte VEGF-A and low endothelial nitric oxide drive the development and the progression diabetic nephropathy. The abnormal cross talk between VEGF-A and NO pathways is fueled by the diabetic milieu increased oxidative stress. Recent findings on these pathogenic molecular mechanisms provide new potential targets for therapy for diabetic renal disease.

Renal Therapeutic Angiogenesis Using a Bioengineered Polymer-Stabilized Vascular Endothelial Growth Factor Construct

“…Together with angiopoietins, these are important promoters of mobilization and homing of cell progenitors, 28 which are crucial steps to achieve angiogenesis that have been shown to be stimulated by VEGF. 29 In addition to the protective effects on the renal MV architecture, intrarenal ELP-VEGF therapy improved glomerular expression of podocin, reduced the excretion of nephrin (both major podocyte slit diaphragm-associated proteins 30,31 ), and reduced albuminuria, implying a reduction in podocyte damage. Since podocytes are both targets and sources of VEGF in the kidney, [32][33][34] ELP-VEGF administration may have in turn stimulated a positive feedback mechanism that could have potentiated podocyte production of VEGF and contributed to renoprotection.…”

New insights on microRNAs in diabetic nephropathy: potential biomarkers for diagnosis and therapeutic targets

“…Так, было показано, что под воздействием гипергликемии снижалась экспрессия miR-93 в подоцитах и эндотелиальных клетках почечных сосудов в клубочках мышей db/db [44]. Это приводило к стимуляции мишени miR-93 -сосудистого эндотели-ального фактора роста А (VEGF-A) -основного регуля-тора ангиогенеза и фактора выживаемости подоцитов, которому придается большое значение в развитии сосу-дистых осложнений и МАУ/ПУ при СД [45].…”

Podocyte-Specific VEGF-A Gain of Function Induces Nodular Glomerulosclerosis in eNOS Null Mice

“…7,17,41,42 Diabetic eNOS KO mice 26,35 and diabetic VEGF 164 gain-of-function mice 6 share similar diabetic milieu and nephropathy pathogenic mechanism (i.e., increased glomerular VEGF-A and eNOS insufficiency), resulting in advanced disease phenotype (i.e., Kimmelstiel-Wilson-like nodular glomerulosclerosis and severe proteinuria). Conversely, nondiabetic mice with intact eNOS and VEGF 164 gain of function develop a phenotype similar to early diabetic nephropathy.…”

“…[1][2][3][4] Glomerular VEGF-A plays a critical role in the pathogenesis of diabetic nephropathy. [5][6][7] Transgenic mice with podocyte VEGF 164 gain of function develop a glomerular phenotype indistinguishable from early diabetic nephropathy, in the context of normal blood glucose and normal systemic VEGF-A. 5 In the setting of type 1 diabetes, plasma VEGF-A increases but nodular glomerulosclerosis develops only in mice with podocyte VEGF 164 gain of function, demonstrating that local rather than systemic VEGF excess is critical for the progression of diabetic glomerulopathy to advanced disease.…”

“…[16][17][18][19][20][21] In diabetes, low NO bioavailability is associated with high VEGF-A levels. 7,8,[22][23][24][25] Nakagawa et al called this process "uncoupling of VEGF to NO," connecting mechanistically the advanced nephropathy with the relationship between VEGF and NO in the kidney. 26 Experimental diabetes induced in eNOS knockout (KO) mice resulted in severe diabetic nephropathy: nodular glomerulosclerosis, decreased GFR, and hypertension, associated with increased VEGF mRNA renal expression.…”