Mitochondrial Dysfunction in Sepsis‐associated Acute Kidney Injury

Abstract

Sepsis-associated acute kidney injury (AKI) is frequently observed and has poor prognosis with no effective treatments. The lack of complete understanding of its pathogenesis is a significant barrier to progress and fresh insights into its pathogenesis are critically needed. We examined renal function by FITC inulin clearance and other functional and molecular analyses to examine mitochondrial dysfunction in the pathogenesis of sepsis using a model of cecal ligation and puncture (CLP) at 24 hours post-injury. We also evaluated therapies targeting mitochondrial dysfunction. GFR was significantly reduced in CLP mice 345±19 vs. 155±35 uL/min; p=0.004. ATP generation was significantly lower in the mitochondria isolated from CLP kidneys along with decreased expression of complex III and complex IV. With western blot expression, we found increased expression of mitochondrial fission proteins DRP1 (p<.0004) and Fis1 (trend for higher expression) in CLP kidneys, indicative of mitochondrial stress. Mitochondrial biogenesis is a compensatory response, but we observed decreased expression of PGC-1α, a key factor in mitochondrial biogenesis and increased expression of autophagy protein, beclin1. We treated mice with P110, a novel inhibitor of fission machinery by blocking the interaction of Fis1 and Drp1 proteins, prior to CLP. P110 treated mice demonstrated significant improvement in GFR 24 hours post CLP compared to untreated mice (255±19 vs. 155 ±35 uL/min; p=0.02). Our findings indicate mitochondrial stress with mitochondrial fission and reduced biogenesis play an important role in the pathogenesis of sepsis associated AKI and targeting this provides a novel therapeutic option. Additional mechanistic investigations to confirm the significance of this pathway are being conducted.