Increased renal oxygen consumption leads to hypoxia in sepsis‐associated acute kidney injury (890.9)

Abstract

We have shown in subtotal nephrectomy (STN), a model of chronic kidney disease, there is increased oxygen consumption (QO2) factored for tubular Na reabsorption (TNa) leading to hypoxia. To demonstrate the universality of hypoxia in the pathogenesis of kidney disease, we have now examined renal oxygenation (oxygen delivery and consumption), mitochondrial function and tubular transport in acute kidney injury (AKI) due to sepsis in a rat model of cecal ligation and puncture (CLP). Data presented as mean±sem.At 6 and 24 hours, GFR was significantly lower in CLP (2.5±0.4 vs. 3.6±0.2 ml/min and 1.2±0.3 vs. 3.3±0.2 ml/min, p<0.001). While RBF and O2 delivery was largely unchanged, renal O2 extraction and QO2 factored for GFR was higher compared to shams, (0.023±0.002 vs. 0.01±0.001 vol%ml/min and 0.11±0.01 vs. 0.05±0.01 ml/min,p<0.04). HIF‐1a expression was upregulated in the CLP kidneys at both 6 and 24 hours. In CLP, we found elevated rates of mitochondrial QO2 (199.9 ± 31.6 pMol/min vs. 163.2 ± 28.81 pMol/min, p<0.05), but significantly lower ATP generation with reduced expression of complex Va and complex III (p<0.05 for both). Proteins regulating mitochondrial morphology were also altered with increased expression of fission protein DRP1 (P<.0004) and decreased expression of PGC‐1alpha, a factor in mitochondrial biogenesis (2.2‐fold lower) in CLP. HIF‐1α activation by DMOG improved GFR at both time points.We demonstrate increased renal QO2 despite lower GFR leading to hypoxia and dissociation between excess QO2 and ATP generation in CLP mitochondria. We are investigating alterations in mitochondrial dynamics which could explain mitochondrial dysfunction and tubular injury, and the role of HIF‐1α pathway in this. In conclusion, our data in both acute and chronic kidney injury model demonstrates early hypoxia due to increased oxygen consumption leading to oxygen demand‐supply mismatch and strongly supports the role of hypoxia as a unifying mechanism for kidney disease.Grant Funding Source: NIH