Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease

Abstract

Vascular endothelial growth factor A (VEGF-A) can play both beneficial and deleterious roles in renal diseases, where its specific function might be determined by nitric oxide bioavailability. The complexity of VEGF-A in renal disease could in part be accounted for by the distinct roles of its two receptors; VEGFR1 is involved in the inflammatory responses, whereas VEGFR2 predominantly mediates angiogenesis. Because nondiabetic chronic renal disease is associated with capillary loss, we hypothesized that selective stimulation of VEGFR2 could be beneficial in this setting. However, VEGFR2 activation may be deleterious in the presence of nitric oxide deficiency. We systematically overexpressed a mutant form of VEGF-A binding only VEGFR2 (Flk-sel) using an adeno-associated virus-1 vector in wild-type and eNOS knockout mice and then induced renal injury by uninephrectomy. Flksel treatment increased angiogenesis and lowered blood pressure in both mouse types. Flk-sel overexpression caused mesangial injury with increased proliferation associated with elevated expression of PDGF, PDGF-␤ receptor, and VEGFR2; this effect was greater in eNOS knockout than in wild-type mice. Flk-sel also induced tubulointerstitial injury, with some tubular epithelial cells expressing ␣-smooth muscle actin, indicating a phenotypic evolution toward myofibroblasts. In conclusion, prestimulation of VEGFR2 can potentiate subsequent renal injury in mice, an effect enhanced in the setting of nitric oxide deficiency.

Blocking VEGF/Caveolin-1 signaling contributes to renal protection of fasudil in streptozotocin-induced diabetic rats

“…Our previous studies demonstrated that the VEGFR2/caveolin-1 association plays an important role in ECM accumulation in mesangial cells [23] . Recent studies have demonstrated that selective stimulation of VEGFR2 accelerates progressive renal disease [42] . Thus, we investigated the effects of fasudil on the association between VEGFR2 and caveolin-1 within the diabetic renal cortex.…”

Peritubular capillary rarefaction: a new therapeutic target in chronic kidney disease

“…In kidney injury induced by angiotensin II infusion followed by a high-salt diet, administration of VEGF-A 121 did not improve PTC rarefaction [79]. In addition, VEGF-A 121 treatment did not improve PTC rarefaction in neonatal mouse kidneys subjected to UUO [80], and systemic overexpression of a mutant form of VEGF-A that can bind only to VEGFR-2 but not to VEGFR-1 enhanced glomerular injury as well as interstitial fibrosis in mice with uninephrectomy [81]. Furthermore, the timing of angiogenic treatment is crucial.…”

A LASSO Method to Identify Protein Signature Predicting Post-transplant Renal Graft Survival

“…VEFG-R2 is one of the receptors of vascular endothelial growth factor A (VEGF-A), which plays an important role in renal disease. Despite many studies that reported VEGF-A to be beneficial in several types of renal injury [37,20,21,35], stimulation of VEGF-R2, however, may be associated with renal injury as it is found to increase in damaged tubular epithelial cells and caused angiogenesis in the kidney [31]. …”