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Mitochondrial biogenesis is regulated by membrane <jats:styled-content style=\"fixed-case\">GTP<\/jats:styled-content>ases, such as optic atrophy factor 1 and mitofusion 2. Here, we investigated whether <jats:styled-content style=\"fixed-case\">SGLT<\/jats:styled-content>2 inhibition in mice fed with a high\u2010fat diet (<jats:styled-content style=\"fixed-case\">HFD<\/jats:styled-content>) improved mitochondrial morphology and restored mitochondrial biogenesis\u2010related molecules.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>Mice were fed a control diet or <jats:styled-content style=\"fixed-case\">HFD<\/jats:styled-content> with or without ipragliflozin treatment. After 16 weeks, the kidneys were taken out and utilized for the analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">HFD<\/jats:styled-content>\u2010fed mice treated with ipragliflozin showed increased caloric intake and ate more food than the control <jats:styled-content style=\"fixed-case\">HFD<\/jats:styled-content>\u2010fed mice. Body and kidney weights, and blood glucose levels were not altered by ipragliflozin treatment in <jats:styled-content style=\"fixed-case\">HFD<\/jats:styled-content>\u2010fed mice. Histological analysis showed that, compared with control mice, <jats:styled-content style=\"fixed-case\">HFD<\/jats:styled-content>\u2010fed mice displayed tubular vacuolation, dilatation and epithelial cell detachment; ipragliflozin ameliorated these alterations. Furthermore, ultrastructural analysis showed that the tubule mitochondria of <jats:styled-content style=\"fixed-case\">HFD<\/jats:styled-content>\u2010fed mice exhibited significant damage. Again, ipragliflozin reversed the damage to a normal state, and restored optic atrophy factor 1 and mitofusion 2 levels in <jats:styled-content style=\"fixed-case\">HFD<\/jats:styled-content>\u2010fed mice. Increased urine 8\u2010hydroxydeoxyguanosine levels in <jats:styled-content style=\"fixed-case\">HFD<\/jats:styled-content>\u2010fed mice were suppressed by ipragliflozin as well. <jats:italic>In vitro<\/jats:italic> experiments using <jats:styled-content style=\"fixed-case\">HK<\/jats:styled-content>\u20102 cells revealed that either high glucose or high palmitate suppressed optic atrophy factor 1 and mitofusion 2 levels. Suppression of <jats:styled-content style=\"fixed-case\">SGLT<\/jats:styled-content>2 by a specific small interfering ribonucleic acid or ipragliflozin restored these <jats:styled-content style=\"fixed-case\">GTP<\/jats:styled-content>ase levels to their normal values.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">SGLT<\/jats:styled-content>2 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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jdi.12802","type":"journal-article","created":{"date-parts":[[2018,1,20]],"date-time":"2018-01-20T05:46:37Z","timestamp":1516427197000},"page":"1025-1032","source":"Crossref","is-referenced-by-count":114,"title":["Ipragliflozin improves mitochondrial abnormalities in renal tubules induced by a high\u2010fat diet"],"prefix":"10.1111","volume":"9","author":[{"given":"Susumu","family":"Takagi","sequence":"first","affiliation":[{"name":"Department of Diabetology &amp; Endocrinology Kanazawa Medical University Uchinada Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinpeng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Diabetology &amp; Endocrinology Kanazawa Medical University Uchinada Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Takagaki","sequence":"additional","affiliation":[{"name":"Department of Diabetology &amp; Endocrinology Kanazawa Medical University Uchinada Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munehiro","family":"Kitada","sequence":"additional","affiliation":[{"name":"Department of Diabetology &amp; Endocrinology Kanazawa Medical University Uchinada Ishikawa Japan"},{"name":"Division of Anticipatory Molecular Food Science and Technology Medical Research Institute Kanazawa Medical University Uchinada Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko","family":"Nitta","sequence":"additional","affiliation":[{"name":"Department of Diabetology &amp; Endocrinology Kanazawa Medical University Uchinada Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiyuki","family":"Takasu","sequence":"additional","affiliation":[{"name":"Drug Discovery Research Astellas Pharma Inc. 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