論文

査読有り
2014年6月

Long-Term Treatment with the Sodium Glucose Cotransporter 2 Inhibitor, Dapagliflozin, Ameliorates Glucose Homeostasis and Diabetic Nephropathy in db/db Mice

PLOS ONE
  • Naoto Terami
  • ,
  • Daisuke Ogawa
  • ,
  • Hiromi Tachibana
  • ,
  • Takashi Hatanaka
  • ,
  • Jun Wada
  • ,
  • Atsuko Nakatsuka
  • ,
  • Jun Eguchi
  • ,
  • Chikage Sato Horiguchi
  • ,
  • Naoko Nishii
  • ,
  • Hiroshi Yamada
  • ,
  • Kohji Takei
  • ,
  • Hirofumi Makino

9
6
開始ページ
e100777
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1371/journal.pone.0100777
出版者・発行元
PUBLIC LIBRARY SCIENCE

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been reported as a new therapeutic strategy for treating diabetes. However, the effect of SGLT2 inhibitors on the kidney is unknown. In addition, whether SGLT2 inhibitors have an anti-inflammatory or antioxidative stress effect is still unclear. In this study, to resolve these issues, we evaluated the effects of the SGLT2 inhibitor, dapagliflozin, using a mouse model of type 2 diabetes and cultured proximal tubular epithelial (mProx24) cells. Male db/db mice were administered 0.1 or 1.0 mg/kg of dapagliflozin for 12 weeks. Body weight, blood pressure, blood glucose, hemoglobin A1c, albuminuria and creatinine clearance were measured. Mesangial matrix accumulation and interstitial fibrosis in the kidney and pancreatic beta-cell mass were evaluated by histological analysis. Furthermore, gene expression of inflammatory mediators, such as osteopontin, monocyte chemoattractant protein-1 and transforming growth factor-beta, was evaluated by quantitative reverse transcriptase-PCR. In addition, oxidative stress was evaluated by dihydroethidium and NADPH oxidase 4 staining. Administration of 0.1 or 1.0 mg/kg of dapagliflozin ameliorated hyperglycemia, beta-cell damage and albuminuria in db/db mice. Serum creatinine, creatinine clearance and blood pressure were not affected by administration of dapagliflozin, but glomerular mesangial expansion and interstitial fibrosis were suppressed in a dose-dependent manner. Dapagliflozin treatment markedly decreased macrophage infiltration and the gene expression of inflammation and oxidative stress in the kidney of db/db mice. Moreover, dapagliflozin suppressed the high-glucose-induced gene expression of inflammatory cytokines and oxidative stress in cultured mProx24 cells. These data suggest that dapagliflozin ameliorates diabetic nephropathy by improving hyperglycemia along with inhibiting inflammation and oxidative stress.


リンク情報
DOI
https://doi.org/10.1371/journal.pone.0100777
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000338633900084&DestApp=WOS_CPL
URL
http://orcid.org/0000-0003-1468-5170
ID情報
  • DOI : 10.1371/journal.pone.0100777
  • ISSN : 1932-6203
  • ORCIDのPut Code : 17913043
  • Web of Science ID : WOS:000338633900084

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