Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease

Abstract

We sought to examine the pathogenic role of excessive VEGF-A expression in podocytes, since it has been reported that diabetic nephropathy and other glomerular diseases are associated with increased VEGF-A expression. The induction of podocyte-specific VEGF164 overexpression in adult transgenic mice led to proteinuria, glomerulomegaly, glomerular basement membrane thickening, mesangial expansion, loss of slit diaphragms, and podocyte effacement. When doxycycline-mediated VEGF164 was stopped, these abnormalities reversed. These findings were associated with reversible downregulation of metalloproteinase 9 and nephrin expression. Using transmission electron microscopy, we established that VEGF-A receptor-2 (VEGFR2) was expressed in podocytes and glomerular endothelial cells. We also found that VEGF164 induced VEGFR2 phosphorylation in podocytes. Further, we were able to co-immunoprecipitate VEGFR2 and nephrin using whole kidney lysates, confirming interaction in vivo. This implies that autocrine and paracrine VEGF-A signaling through VEGFR2 occurs in podocytes and may mediate the glomerular phenotype caused by VEGF164 overexpression. Thus, we suggest that podocyte VEGF164 overexpression in adult mice is sufficient to induce glomerular filtration barrier structural and functional abnormalities similar to those present in murine diabetic nephropathy.

Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease

“…Veron et al 43 documented that overexpression of VEGF-A in podocytes stimulates VEGFR2 expression in autocrine fashion, whereas our experiments showed that VEGFR2 stimulation did not affect podocyte structure. The most likely explanation for this discrepancy is that VEGF-A was locally overexpressed in podocytes themselves in the Veron et al 43 study, but Flk-sel levels were increased in the circulation in the present study. The concentration of Flk-sel could presumably be reduced when it reaches podocyte cells.…”

Urinary excretion of angiogenesis regulatory factors and renal injury markers in chronic glomerulonephritis: Significance in the assessment of progression

“…Так, установлено, что VEGF-A (а возможно, и другие регулято-ры ангиогенеза), вырабатываемый в подоцитах, по пара-кринному механизму взаимодействует с эндотелием клу-бочков, увеличивая его фенестрацию и таким образом способствует повышению ПУ [7,24].…”

Low-grade risk of hypercoagulable state in patients suffering from diabetes mellitus type 2

“…VEGF is crucial for maintaining the homeostasis of renal hemodynamics (Xu et al, 2012). However, VEGF overexpression in the glomerular podocytes is connected with an enhanced vascular permeability in glomerulus for macromolecules and an increased albuminuria and, consequently, proteinuria, leading to glomerular hypertrophy (Kubisz et al, 2010;Veron et al, 2010;Kota et al, 2012).…”

“…Diabetes is also the most significant cause of end-stage renal failure worldwide. Clinically, glomerular hyperfiltration and microalbuminuria develop and, as a consequence, cause overt proteinuria and a reduced number of functioning nephrons, leading to renal failure (Kubisz et al, 2010;Veron et al, 2010).…”