Ipragliflozin improves mitochondrial abnormalities in renal tubules induced by a high‐fat diet. Issue 5 (12th March 2018) - Takagi, Susumu
Abstract: Aims/Introduction: Complete mechanisms of renoprotective effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors have not been elucidated yet. Mitochondrial biogenesis is regulated by membrane GTPases, such as optic atrophy factor 1 and mitofusion 2. 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 a control diet or HFD with or without ipragliflozin treatment. After 16 weeks, the kidneys were taken out and utilized for the analysis. Results: HFD‐fed mice treated with ipragliflozin showed 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 showed that, compared with control mice, HFD‐fed mice displayed tubular vacuolation, dilatation and epithelial cell detachment; ipragliflozin ameliorated these alterations. Furthermore, ultrastructural analysis showed that the tubule mitochondria of HFD‐fed mice exhibited significant damage. Again, ipragliflozin reversed the damage to a normal state, and restored optic atrophy factor 1 and mitofusion 2 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 optic atrophy factor 1 and mitofusion 2 levels. Suppression of SGLT2 by a specific small interfering ribonucleic acid or ipragliflozin restored these GTPase levels to their normal values. Conclusions: SGLT2 inhibition might act directly on tubular cells and protect kidney tubular cells from mitochondrial damage by metabolic insults regardless of blood glucose levels or improvement in bodyweight reduction. Abstract : SGLT2 inhibitor ipragliflozin ameliorated mitochondrial homeostasis in the kidney tubule of ad libitum HFD‐fed mice. Ipragliflozin did not reduce body weight or blood glucose levels in ad libitum HFD‐fed mice. Beneficial effects of ipragliflozin on kidney tubule mitochondria were associated with the restoration of Opa1 and Mfn2 levels.