Journal of diabetes investigation 2018 01 20() doi 10.1111/jdi.12802
Complete mechanisms of reno-protective effects of SGLT2 inhibitors have not been elucidated yet. Mitochondrial biogenesis is regulated by membrane GTPases, such as Opa1 and Mfn2. Here, we investigated whether SGLT2 inhibition in mice fed with a high-fat diet (HFD) improved mitochondrial morphology and restored mitochondrial biogenesis-related molecules.
MATERIALS AND METHODS
Mice were fed in control diet or HFD with or without ipragliflozin treatment. After 16 weeks, the kidneys were taken out and utilized for the analysis.
HFD-fed mice treated with ipragliflozin exhibited increased caloric intake and ate more food than the control HFD-fed mice. Body and kidney weights and blood glucose levels were not altered by ipragliflozin treatment in HFD-fed mice. Histological analysis revealed that, however compared to control mice, HFD-fed mice displayed tubular vacuolation, dilatation and epithelial cell detachment; ipragliflozin ameliorated these alterations. Furthermore, ultrastructural analysis demonstrated that the tubule mitochondria of HFD-fed mice exhibited significant damage. Again, ipragliflozin reversed the damage to a normal state and restored Opa1 and Mfn2 levels in HFD-fed mice. Increased urine 8-hydroxydeoxyguanosine levels in HFD-fed mice were suppressed by ipragliflozin as well. In vitro experiments using HK-2 cells revealed that either high glucose or high palmitate suppressed Opa1 and Mfn2 levels. Suppression of SGLT2 by a specific siRNA or ipragliflozin restored these GTPase levels to their normal values.
SGLT2 inhibition may act directly on tubular cells and protect kidney tubular cells from mitochondrial damage by metabolic insults regardless of blood glucose levels or improvement in body weight reduction. This article is protected by copyright. All rights reserved.