Pathophysiological Role of Vascular Endothelial Growth Factor in the Remnant Kidney

Abstract

Background: Subtotal renal ablation is characterized by initial glomerular hypertrophy, followed by progressive development of glomerulosclerosis and interstitial fibrosis. Vascular endothelial growth factor (VEGF) is involved in glomerular hypertrophy and dysfunction in several pathophysiological conditions. On the other hand, progressive glomerulosclerosis and tubulo-interstitial fibrosis in the remnant kidney have been associated with loss of VEGF expression. Methods: To explore the pathophysiological role of VEGF in the development of glomerular hypertrophy and renal damage in the remnant kidney model, we examined the effect of a neutralizing VEGF antibody on glomerular volume and kidney function in rats after subtotal nephrectomy or sham operation. Erythropoietin was administered to exclude a confounding effect of anaemia. Results: Six weeks after subtotal nephrectomy, plasma urea and creatinine concentrations, urinary albumin excretion, and mean glomerular volume were elevated in the placebo-treated uraemic rats as compared with the sham-operated rats. Inhibition of VEGF partially prevented the glomerular hypertrophy and largely prevented the rise in urinary albumin excretion, but did not affect creatinine clearance in uraemic rats. Conclusions: VEGF is a mediator of glomerular hypertrophy after subtotal renal ablation. In view of glomerular hypertrophy as the initial deleterious event ultimately leading to progressive glomerulosclerosis, agents that block this glomerular growth could be useful in preventing scarring in progressive renal disease.

Mammalian Target of Rapamycin Inhibition Halts the Progression of Proteinuria in a Rat Model of Reduced Renal Mass

“…Whether modulation of the VEGF system (e.g., through the use of an mTOR inhibitor) leads to a negative effect, as observed by Daniel et al, 23 or to a beneficial consequence, as observed by Schrijvers et al 13 or in our model, might depend on the type of damage and the timing of the treatment. It is imaginable that VEGF might be needed for endothelial repair for a short period and later exert negative effects in terms of favoring glomerular hypertrophy and fibrotic mechanisms.…”

“…VEGF has also been proposed to play a significant role in the development of glomerular hypertrophy and albuminuria in the model of renal ablation, which could be shown by Schrijvers et al 13 In their study, the administration of a neutralizing VEGF antibody directly after renal mass reduction had a beneficial effect by significantly attenuating the increase of albuminuria and glomerular hypertrophy.…”

“…Two of these groups were assigned to undergo renal mass reduction and the other two to have sham operations. Renal mass reduction was performed by cryoablation and subsequent contralateral uninephrectomy after 1 wk, as published by Schrijvers et al 13 The rats of the sham groups underwent surgery at the same time points. These procedures were performed under general anesthesia with isofluorane (Forane; Abbott Laboratories, S.A., Madrid, Spain).…”

“…This can be prevented by early VEGF antagonism. 13 Conversely, late after renal mass reduction, the VEGF system is downregulated and external VEGF application improves renal function. 14 Thus, the VEGF system is regulated according to specific pathologic situations.…”

Therapeutic Potential of Angiostatin in Diabetic Nephropathy

“…The glomerular areas were measured using SPOT Advanced Software (Diagnostic Instruments, Inc., Sterling Heights, MI) and averaged from 120 to 150 glomeruli per kidney (34). The glomerular volume was calculated by the formula V G ϭ area 1.5 ϫ 1.38/1.1 (35). The cell numbers in glomeruli were counted, and the average glomerular cell number was obtained from 100 glomeruli per kidney.…”