Journal
JOURNAL OF DIABETES INVESTIGATION
Volume 9, Issue 5, Pages 1025-1032Publisher
WILEY
DOI: 10.1111/jdi.12802
Keywords
High-fat diet; Mitochondria; Sodium-glucose cotransporter 2
Categories
Funding
- Astellas Pharma Inc.
- Japan Society for the Promotion of Science [23790381, 25282028, 25670414]
- Kanazawa Medical University [S2015-3, S2016-3, S2017-1]
- Grants-in-Aid for Scientific Research [23790381, 25282028] Funding Source: KAKEN
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Aims/IntroductionComplete 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 MethodsMice 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. ResultsHFD-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. ConclusionsSGLT2 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.
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