515-P: Mitochondrial AKT1 in Renal Tubules Is a Novel Modulator for the Development of Glomerulosclerosis and Subsequent Renal Failure

Abstract

Diabetes increases the risk of renal ischemia/reperfusion injury (IRI). Recent evidence suggests that tubular dysfunction is associated with glomerular impairment, but its causal relationship is unclear. Renal tubules have abundant mitochondria; Akt is translocated into mitochondria upon IRI. To test the hypothesis that tubular mitochondrial Akt1 (mito-Akt) plays a protective role during IRI and subsequent renal failure, we have generated novel renal tubule-specific transgenic mice harboring inducible mitochondria-targeting dominant negative Akt1 (KMDAKT) or constitutively active Akt1 (KMCAKT) with the Cre-lox system. After KMDAKT mice were induced with tamoxifen (T) and subjected to IRI, histological analysis showed increased tubule injury index Jablonski score (p<0.04) and greater renal fibrosis as compared to the corn-oil (CO) injected mice (p<0.02). Kidney Injury Molecule-1 (KIM1), PAS-positive glomerulosclerosis, and serum creatinine were all increased (p<0.01) in the T-KMDAKT mice when compared to the CO mice 45-days post IRI. Renal inflammatory markers, including IL-1B, were also increased, suggesting inflammation played a role. Kaplan-Meier analysis showed much lower survival in the T-KAMDAKT mice post IRI than the CO mice (p<0.01). To study whether augmentation of tubular mito-Akt can protect against renal IRI, T-KMCAKT and CO-KMCAKT were subjected to renal IRI.T-KMCAKT mice showed an improved Jablonski score (p<0.02), less renal fibrosis (p<0.04), and lower KIM1 expression (p<0.02). T-KMCAKT mice exhibited less glomerulosclerosis and better survival (p<0.01). Summary: 1] tubular mito-Aktcritically modulated the outcomes of kidney IRI beyond renal tubules, 2] tubular mitochondria dysfunction causally triggered development of glomerulosclerosis during acute and chronic kidney failure, and 3] renal tubular mito-Akt, which is activated by insulin, may represent a novel therapeutic target for diabetic nephropathy. Disclosure H.Y. Lin: None. Y. Chen: None. A. Ta: None. H. Lee: None. Y. Chen: None. P.H. Wang: None.