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Clinical data suggest that improved renal outcomes by Na<jats:sup>+<\/jats:sup>-glucose cotransporter 2 inhibitor (SGLT2i) are partly beyond their antihyperglycemic effects; however, the mechanisms are still elusive. Here, we investigated the effect of the SGLT2i dapagliflozin (DAPA) in the prevention of elevated O-GlcNAcylation and tubular hypoxia as contributors of renal fibrosis. Type 1 diabetes was induced by streptozotocin in adult male Wistar rats. After the onset of diabetes, rats were treated for 6 wk with DAPA or DAPA combined with losartan (LOS). The effect of hyperglycemia was tested in HK-2 cells kept under normal or high glucose conditions. To test the effect of hypoxia, cells were kept in 1% O<jats:sub>2<\/jats:sub> for 2 h. Cells were treated with DAPA or DAPA combined with LOS. DAPA slowed the loss of renal function, mitigated renal tubular injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and reduced tubulointerstitial fibrosis. DAPA diminished high glucose-induced protein O-GlcNAcylation and moderated the tubular response to hypoxia through the hypoxia-inducible factor pathway. DAPA alone was as effective as combined treatment with LOS in all outcome parameters. These data highlight the role of ameliorated O-GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia, and fibrosis, a vicious trio that could be targeted by SGLT2i in kidney diseases of other origins as well. <\/jats:p>","DOI":"10.1152\/ajprenal.00021.2020","type":"journal-article","created":{"date-parts":[[2020,3,2]],"date-time":"2020-03-02T12:06:17Z","timestamp":1583150777000},"page":"F1017-F1029","source":"Crossref","is-referenced-by-count":54,"title":["Reduced <i>O<\/i>-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney"],"prefix":"10.1152","volume":"318","author":[{"given":"Judit","family":"Hodrea","sequence":"first","affiliation":[{"name":"MTA-SE \u201cLend\u00fclet\u201d Diabetes Research Group, Hungarian Academy of Sciences, Budapest, Hungary"},{"name":"1st Department of Pediatrics, Semmelweis University, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dora 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