Background: SGLT2 inhibitor (SGLT2i) displayed remarkable and early renal protection in overt nephropathy cases in clinical trials. However, detailed molecular mechanisms by which SGLT2i ameliorated renal damage in proteinuric diabetic patients were not elucidated yet. Here, we investigated that SGLT2i exerted renal protective effects via adenosine signal in diabetic mice with overt proteinuria.

Methods: STZ (200mg/kgBW) was injected intraperitoneally to induce diabetes in 8-week-old CD-1 mice. Four weeks later, mice were treated with intraperitoneal injection of bovine serum albumin (BSA: 0.3g/30gBW) with or without oral administration of SGLT2i TA-1887 (30mg/kg).

Result: In the STZ+BSA, pronounced renal tubular damages and interstitial fibrosis were observed; TA-1887 significantly ameliorated. The mRNA microarray analysis of kidney samples revealed that gene expressions related to TGF-β signaling pathway and epithelial-mesenchymal-transition program were increased in the STZ+BSA compared to the Control+BSA; TA-1887 suppressed them. Furthermore, the expression of ecto 5'-nucleotidase (5'-NT), which is essential for production of adenosine from AMP, was suppressed in STZ+BSA compared to Control+BSA; TA-1887 restored 5’-NT levels. In the immunohistological analysis, 5'-NT was expressed in glomeruli including mesangial cells and renal tubules of cortex/medulla in control kidney. However, 5’-NT was suppressed in all areas of STZ+BSA kidney; TA-1887 reversed the 5'-NT expression and distribution. Glomerular filtration rate (GFR) evaluated by inulin clearance was significantly greater in the STZ+BSA group and suppressed by TA-1887; the administration of the adenosine type 1 receptor inhibitor, DPCPX, cancelled the effects of TA-1887 on GFR and renal tubule damage.

Conclusion: The adenosine signal plays an important role in the renal protective effects of SGLT2i in diabetic mice with proteinuria.


K. Shimada: None. Y. Takagaki: None. K. Kanasaki: Other Relationship; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Taisho Toyama Pharmaceutical. D. Koya: Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Astellas Pharma Inc., Astellas Pharma Inc., AstraZeneca, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Taisho Pharmaceutical Co., Ltd.


Japan Society for the Promotion of Science

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at