Tubular Deficiency of von Hippel-Lindau Attenuates Renal Disease Progression in Anti-GBM Glomerulonephritis

Abstract

In many kidney diseases, the original insult primarily involves the glomerulus and may then pass onto the tubulointerstitium. Several hypotheses link glomerular disease to tubular injury; perhaps the foremost hypothesis involves chronic tubular hypoxia. The reported effects of hypoxia and consecutive stabilization of hypoxia-inducible factors (HIFs), however, are controversial. Hypoxia induces interstitial fibrosis but also has beneficial effects on renal disease progression when HIF is activated pharmacologically. To analyze the impact of HIF on tubulointerstitial disease development in primary glomerular disease, transgenic von Hippel Lindau (VHL)-knockout mice were generated and null expression was induced before the onset of autoimmune IgG-mediated anti-glomerular basement membrane glomerulonephritis (GN). Tubular VHL knockout and, thus, local HIF-α stabilization increased renal production of vascular endothelial growth factor, tumor growth factor-β(1), and platelet-derived growth factor-B, resulting in augmented formation of capillaries and interstitial matrix, and conversion of fibroblasts to myofibroblasts. Within the glomerular disease, VHL knockout reduced the glomerular damage and attenuated tubulointerstitial injury. Likewise, proteinuria, plasma urea concentration, and tubulointerstitial matrix were decreased in VHL knockout with GN. These findings shown that tubular HIF-α stabilization in glomerular disease is beneficial for disease outcome. In comparison with VHL knockout alone, GN is a much stronger activator of fibrosis such that stimuli other than hypoxia may be considered important for renal disease progression.

Central Role for Endothelial Human Deneddylase-1/SENP8 in Fine-Tuning the Vascular Inflammatory Response

“…Additionally, work by Song et al demonstrated protective influences of pharmacological HIF induction in the kidney using DMOG, a known HIF stabilizer (51). Likewise, constitutive activation of HIF dampens glomerulonephritis progression, providing further evidence for beneficial influences of HIF for renal injury (52). Our results extend these findings to a murine model of septic renal injury, emphasizing the importance of renal HIF stabilization during kidney injury and hinting at potential beneficial influences of MLN4924 in various nephropathies.…”

Role of hypoxia in progressive chronic kidney disease and implications for therapy

“…Furthermore, knocking out pVHL in the thick ascending limb, which causes local HIF accumulation, significantly attenuated proximal tubular injury following ischemia-reperfusion by enhancing the glycolytic enzymes and lactate metabolism [39]. The conditional knockout of pVHL in tubular cells attenuated tubulointerstitial injury in anti-glomerular basement membrane glomerulonephritis by enhancing the angiogenic factors and growth factors [40]. The activation of HIF in infiltrating myeloid cells by VHL-conditional knockout suppressed inflammation in the UUO model [38].…”

Tubulovascular Cross-Talk by Vascular Endothelial Growth Factor A Maintains Peritubular Microvasculature in Kidney

“…Myofibroblast formation in kidney may depend on environmental cues, such as the presence of inflammatory molecules. 5 Alternatively, normalization of hematocrit in Vegfa tub mice could be envisioned to promote enhanced stabilization of hypoxia-inducible factors and augment the expression of their target genes, such as plateletderived growth factor, 24 which has previously been shown to be important for myofibroblast formation. 25 Whether the myofibroblasts are derived from REPs or other cell types remains to be determined.…”