Diabetic nephropathy is a major cause of end-stage renal disease. We have recently shown translocation of AKT to mitochondria in proximal tubules played a renoprotective role in murine ischemia/reperfusion injury. In this study, we tested the hypothesis that activation of mitochondrial AKT (mito-AKT) signaling in renal proximal tubules improves kidney function in diabetic nephropathy and modulates overall glucose homeostasis. We used renal tubule-specific bigenic mice that harbor tamoxifen-inducible mitochondria-targeting constitutively active AKT1 (KMCAKT), which were fed with either normal chow diet or high fat and fructose diet (HFFD). Wild type mice fed with HFFD developed nephropathy after 24 wks. Activation of renal tubular mito-AKT significantly attenuated urinary albumin, creatinine, and glucose excretion in the KMCAKT mice on HFFD. Interestingly, activation of tubular mito-AKT also decreased fasting hyperglycemia, and improved glucose tolerance of HFFD-fed mice. Insulin resistance (HOMA-IR) was significantly reduced when tubular mito-AKT was activated. In addition, mito-AKT activation reduced plasma cholesterol. Furthermore, mito-AKT activation increased total body weight and fat mass of HFFD-fed mice, but had no effect on their water and food intake. To dissect the underlying mechanism, we used 18F-fluoro-4-thia-oleate PET scan to define organ specific fatty acid uptake, and revealed a significant increase of uptake in white and brown adipose tissues in KMCAKT mice on HFFD. In conclusion, this is the first report to demonstrate critical roles of mitochondrial AKT in renal tubules in the regulation of whole-body metabolism, insulin sensitivity, and body composition beyond its local effect on kidney function in diabetic nephropathy, which suggests kidney function and nephropathy associated metabolic dysfunction could be mediated through a common pathway in tubular mitochondria.


E.Salem: None. A.Ta: None. H.Y.H.Lin: None. J.Li: None. P.H.Wang: Research Support; ViaCyte, Inc.


Shannon & Amy Ko Foundation

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.