Papers

International journal
Aug, 2016

Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice.

Pharmacology research & perspectives
  • Takashi Hatanaka
  • ,
  • Daisuke Ogawa
  • ,
  • Hiromi Tachibana
  • ,
  • Jun Eguchi
  • ,
  • Tatsuyuki Inoue
  • ,
  • Hiroshi Yamada
  • ,
  • Kohji Takei
  • ,
  • Hirofumi Makino
  • ,
  • Jun Wada

Volume
4
Number
4
First page
e00239
Last page
Language
English
Publishing type
Research paper (scientific journal)
DOI
10.1002/prp2.239

It is unclear whether the improvement in diabetic nephropathy by sodium glucose cotransporter 2 (SGLT2) inhibitors is caused by a direct effect on SGLT2 or by the improvement in hyperglycemia. Here, we investigated the effect of dapagliflozin on early-stage diabetic nephropathy using a mouse model of type 1 diabetes and murine proximal tubular epithelial cells. Eight-week-old Akita mice were treated with dapagliflozin or insulin for 12 weeks. Body weight, urinary albumin excretion, blood pressure, as well as levels of blood glucose and hemoglobin A1c were measured. Expansion of the mesangial matrix, interstitial fibrosis, and macrophage infiltration in kidneys were evaluated by histology. Oxidative stress and apoptosis were evaluated in kidneys and cultured proximal tubular epithelial cells. Compared with nontreated mice, dapagliflozin and insulin decreased blood glucose and hemoglobin A1c levels equally. Urine volume and water intake increased significantly in the dapagliflozin-treated group compared with those in the insulin-treated group, but there were no differences in body weight or blood pressure between the two groups. Macrophage infiltration and fibrosis in renal interstitium improved significantly in the dapagliflozin group compared with the insulin group. Oxidative stress was attenuated by dapagliflozin, and suppression occurred in a dose-dependent manner. RNAi knockdown of SGLT2 resulted in reduced oxidative stress. Dapagliflozin ameliorates diabetic nephropathy by suppressing hyperglycemia-induced oxidative stress in a manner independent of hyperglycemia improvement in Akita mice. Our findings suggest that dapagliflozin may be a novel therapeutic approach for the treatment of diabetic nephropathy.

Link information
DOI
https://doi.org/10.1002/prp2.239
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/28116093
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242174
ID information
  • DOI : 10.1002/prp2.239
  • Pubmed ID : 28116093
  • Pubmed Central ID : PMC5242174

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