UC Irvine

Acute kidney injury (AKI) is a significant public health issue with high morbidity and mortality. Recent evidences suggest that renal tubular dysfunction may modulate glomerular function; however, its mechanism remains unknown. We hypothesized that mitochondrial AKT1 signaling could play a protective role in the pathogenesis of AKI and subsequent kidney failure. We have generated novel renal tubular cell-specific transgenic mice harboring an inducible mitochondria-targeting dominant negative AKT1 (KMDAKT) or constitutively active AKT1 (KMCAKT) with Cre-lox strategy. AKI was induced by ischemia-reperfusion injury (IRI). IRI induced greater renal injury with increased Jablonski score (p=0.018), an index of overall renal tubular injuries, in the tamoxifen (TAM)-injected KMDAKT mice. Renal fibrosis areas (%) by Masson’s trichrome stain was significantly larger in the KMDAKT mice as compared to the control mice (p<0.001). Marker for renal tubule injury (kidney injury molecule-1, KIM-1) was significantly increased in the KMDAKT mice (p=0.002). Grades of Periodic acid Schiff (PAS) stain of glomerulosclerosis were significantly higher on day 45 post AKI in the TAM-KMDAKT (p<0.001). Creatinine (Cr.) was significantly higher in the TAM-KMDAKT group 45 days post AKI (p<0.001). Survival rate was significantly lower in the TAM-MDAKT mice 7 days post ischemia (46.67%) as compared to the controls (85.71%) (p=0.0013). To study whether enhancing tubule mitochondrial AKT1 signaling can further protect kidney injury, we used KMCAKT mice as our experimental model. Histology analysis confirmed lesser renal injury with decreased Jablonski score after AKI (p=0.038). Renal fibrosis areas (%) was significantly smaller when compared to the control mice (p=0.002). KIM-1 were decreased in the KMCAKT mice (p<0.001). PAS stain of glomerulosclerosis were significantly lower in the TAM injected KMCAKT mice45 days post AKI (p<0.001). Survival rate in the TAM-KMCAKT mice after AKI was improved (p<0.001). Mitochondria respiration was investigated and the results showed increased basal respiration (p<0.001), spare respiration (p<0.001), adenosine triphosphate (ATP) dependent respiration (p<0.001), and proton leak in the KMDAKT tubule cells. Activation of mitochondrial AKT1 signaling protected kidney injury from glomerulosclerosis after IRI through attenuating renal tubular damage, therefore, mitochondrial AKT1 is a novel target for therapeutic intervention to prevent AKI and subsequent development of CKD.