Peritubular Capillary Loss after Mouse Acute Nephrotoxicity Correlates with Down-Regulation of Vascular Endothelial Growth Factor-A and Hypoxia-Inducible Factor-1α

Abstract

Although the response of kidneys acutely damaged by ischemia or toxins is dominated by epithelial destruction and regeneration, other studies have begun to define abnormalities in the cell biology of the renal microcirculation, especially with regard to peritubular capillaries. We explored the integrity of peritubular capillaries in relation to expression of vascular endothelial growth factor (VEGF)-A, hypoxia-inducible factor (HIF)-alpha proteins, and von Hippel-Lindau protein (pVHL) in mouse folic acid nephropathy, a model in which acute tubular damage is followed by partial regeneration and progression to patchy chronic histological damage. Throughout a period of 14 days, in areas of cortical tubular atrophy and interstitial fibrosis, loss of VEGFR-2 and platelet endothelial cell adhesion molecule-expressing peritubular capillaries was preceded by marked decreases in VEGF-A transcript and protein levels. Nephrotoxicity was associated with tissue hypoxia, especially in regenerating tubules, as assessed by an established in situ method. Despite the hypoxia, levels of HIF-1 alpha, a protein known to up-regulate VEGF-A, were reduced. During the course of nephrotoxicity, levels of pVHL, a factor that destabilizes HIF-1 alpha, increased significantly. We speculate that that down-regulation of VEGF-A may be functionally-implicated in the progressive attrition of peritubular capillaries in areas of tubular atrophy and interstitial fibrosis; VEGF-A down-regulation correlates with a loss of HIF-1 alpha expression which itself occurs in the face of increased tissue hypoxia.