Previously, we found that mild tubulointerstitial injury sensitizes glomeruli to
subsequent injury. Here, we evaluated whether stabilization of
hypoxia-inducible factor-α (HIF-α), a key regulator of tissue response to
hypoxia, ameliorates tubulointerstitial injury and impact on subsequent glomerular injury. Nep25 mice, which express the human CD25 receptor on podocytes under control of the
nephrin promotor and develop glomerulosclerosis when a specific toxin is administered were used. Tubulointerstitial injury, evident by week two, was induced by
folic acid, and mice were treated with an HIF stabilizer,
dimethyloxalylglycine or vehicle from week three to six. Uninephrectomy at week six assessed tubulointerstitial
fibrosis. Glomerular injury was induced by podocyte toxin at week seven, and mice were sacrificed ten days later. At week six tubular injury markers normalized but with patchy
collagen I and interstitial
fibrosis.
Pimonidazole staining, a
hypoxia marker, was increased by
folic acid treatment compared to vehicle while
dimethyloxalylglycine stimulated HIF-2α expression and attenuated tubulointerstitial
hypoxia. The hematocrit was increased by
dimethyloxalylglycine along with downstream effectors of HIF. Tubular epithelial cell injury,
inflammation and interstitial
fibrosis were improved after
dimethyloxalylglycine, with further reduced mortality, interstitial
fibrosis, and glomerulosclerosis induced by specific podocyte injury. Thus, our findings indicate that
hypoxia contributes to tubular injury and consequent sensitization of glomeruli to injury. Hence, restoring HIFs may blunt this adverse crosstalk of tubules to glomeruli.