Diabetes increases the risks of ischemia/reperfusion kidney injury, but the etiology is not known. Mitochondrial dysfunction, which can be modulated by AKT1, may play a critical role in nephropathy and subsequent kidney failure. We hypothesized that impaired mitochondrial AKT1 signaling plays a mechanistic role in the pathogenesis of kidney injury. Insulin acutely stimulated AKT1 translocation from the cytosol to mitochondria in renal proximal tubules, however, the translocation was impaired in diet-induced diabetes. In our murine kidney ischemia-reperfusion injury (IRI) model (30 min ischemia followed by reperfusion), serum BUN increased by 2-fold (p=0.001) and creatinine by 5-fold (p=0.038). The Jablonski score of renal tubular injury was significantly elevated after reperfusion (24 hours, p=0.0004; 1 week, p=0.027). Renal fibrosis (% area) in the IRI mice was significantly higher than the sham control mice (p<0.001). Rapid accumulation of phyosphorylated AKT1 in the mitochondria at proximal tubules were found 30 minutes (p=0.0303) and 60 minutes (p=0.0173) after IRI. AKT1 translocation to IRI renal tubule mitochondria was confirmed with confocal microscope and western blots of mitochondria proteins. To further dissect the role of mitochondrial AKT1 signaling during IRI in the renal tubules, we have generated novel renal tubule-specific transgenic mice harboring an inducible mitochondria-targeting dominant negative AKT1 (KiDAKT) with cre-lox strategy. After tamoxifen induction, markers for renal tubule injuries (KIM-1, and CD44) were significantly increased in the KiDAKT mice. Histology analysis confirmed renal injury with increased Jablonski score. Therefore, inhibition of mitochondrial AKT1 signaling led to development kidney injury. These findings shed new light into the mechanistic role of mitochondrial AKT1 in nephropathy, and mitochondria signaling may become a novel target to develop new strategies for the prevention and treatment of kidney diseases.
H. Lin: None. Y. Chen: None. Y. Chen: None. A. Ta: None. H. Lee: None. P.H. Wang: None.