Increased Expression of Vascular Endothelial Growth Factor in Kidney Leads to Progressive Impairment of Glomerular Functions

Abstract

Vascular endothelial growth factor (VEGF) is an important mediator in maintaining normal kidney functions. In addition, several lines of evidence suggest that upregulation of VEGF in glomeruli may be associated with or cause renal dysfunction such as diabetic nephropathy. For elucidation of the pathologic consequences of high levels of VEGF in glomeruli, transgenic (Tg) rabbits that express human VEGF 165 isoform in both kidney and liver under the control of the human ␣-1-antitrypsin promoter were generated and characterized. With the use of heterozygous Tg rabbits and their littermates aged 8 to 55 wk, renal functions and structures were investigated. Compared with control rabbits, Tg rabbits exhibited progressive proteinuria with increased GFR at the early stage and decreased GFR at the later stage. Histologic examinations revealed that Tg rabbit kidneys were characterized by considerable glomerular hypertrophy as a result of increased proliferation of both glomerular capillaries and mesangial cells accompanied by prominent podocyte hypertrophy. With increasing age starting from 20 wk, Tg rabbit kidneys showed prominent formation of microaneurysms and capillary proliferation at the vascular pole area. At a later stage (55 wk), many glomeruli showed sclerosis and tuft collapse with the formation of glomerular cysts on a background of tubular atrophy and interstitial fibrosis. This study provides the first evidence that increased expression of VEGF in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria, suggesting that VEGF exerts multiple effects on the glomerular pathophysiologic processes.

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

“…6 Further, overproduction of VEGF in transgenic animals is sufficient to resemble the glomerular alterations seen in DN. 7,8 Moreover, biopsies from type 1 and type 2 diabetic patients with early renal damage show an increased glomerular VEGF. [9][10][11][12][13] Therefore, identification of upstream mediators of VEGF overproduction is critical for identifying the pathogenesis of this disease.…”

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

“…46 VEGF also mediates renal hypertrophy, increases in GFR, and urinary protein excretion in early diabetic nephropathy. 61 The functional role of Adora2b signaling on VEGF release has been controversial, with some studies showing VEGF promotion and other studies showing VEGF reduction. 62,63 To our knowledge, the present studies provide the first genetic evidence for a functional role of Adora2b signaling in attenuating renal VEGF levels.…”

Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

“…12,[24][25][26] Importantly, postmitotic podocytes exhibit high levels of basal autophagy as a key regulator of podocyte and glomerular maintenance. 13 Additionally, a strong body of evidence supports the role for maintenance of endothelial function in diabetes to limit DN progression involving homeostasis of multiple systems 7,[27][28][29][30] such as NOS3/eNOS (nitric oxide synthase 3 [endothelial cell]) activity, 31 glycocalyx production, 32,33 EDN/endothelin actions [34][35][36][37][38] and balanced VEGF (vascular endothelial growth factor) 33,39,40 and ANGPT/angiopoietin systems. 41 Endothelial cells may also use autophagy as a coping mechanism to metabolic stress.…”