Mechanisms Up- and Down-Stream of Hypoxia-Inducible Factor in Acute Kidney Injury

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At present, no specific therapy exists for either evolving or established acute kidney injury (AKI). Altered regional renal hemodynamics play an important role in AKI. Recent studies, including those from our group, suggest that activation of hypoxia-inducible transcription factors (HIFs) can alleviate experimental AKI. Most of these studies used renal artery clamping to induce ischemia and reperfusion injury (I/RI). Importantly, HIF activation was commonly achieved before the onset of AKI. The potential impact on renal hemodynamics has not been studied. In a preliminary study in transgenic mice, we found that activation of HIF through an inducible knockout of the von Hippel Lindau protein (pVHL), starting 4 wk before the insult, enhances renal tubulo-interstitial capillarization and ameliorates acute tubular injury in experimental rhabdomyolysis. The rhabdomyolosis model closely resembles the human syndrome of AKI induced by crush injury. In the present proposal, we attempt to investigate 1) whether renal protection may be achieved with HIF activation shortly before or even after the onset of injury, 2) which HIF target genes associate with protection from AKI, 3) the contribution of improved capillarization to renal protection, 4) the potential role of novel non-invasive magnetic resonance imaging techniques for early diagnose, risk stratification, and control of HIF activating therapy in AKI, 5) the effects of myoglobin and HIF on glomerular hemodynamics. Taken together, this study will evaluate the therapeutic potential of HIF activation in a clinically representative mouse model of AKI.