Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes

作者：Tang Li; Wu Yuanyuan; Tian Mi; Sjostrom C David; Johansson Ulrika; Peng Xiao Rong; Smith David M; Huang Yufeng^*

来源：American Journal of Physiology - Endocrinology And Metabolism, 2017, 313(5): E563-E576.

DOI：10.1152/ajpendo.00086.2017

• sodium glucose co-transporter type 2 inhibitors
• type 2 diabetes
• albuminuria
• renal fibrosis
• liver fibrosis

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic oral agents indicating promising effects on cardiovascular and renal end points. However, the renoprotective effects of SGLT2 inhibitors are not fully understood. Also, metabolic effects of SGLT2 inhibition on other organ systems, such as effects on hepatic steatosis, are not fully understood. This study sought to address these questions by treating 18-wk-old uninephrectomized db/db mice with the selective SGLT2 inhibitor dapagliflozin. Untreated db/db mice developed progressive albuminuria, glomerular mesangial matrix expansion, and fatty liver associated with increased renal expression of TGF beta 1, PAI-1, type IV collagen and fibronectin, and liver deposition of fibronectin, type I and III collagen, and laminin. Treatment with dapagliflozin (1 mg.kg(-1).day(-1)) via gel diet from 18 to 22 wk of age not only reduced blood glucose (371.14 +/- 55.02 mg/dl in treated db/db vs. 573.53 +/- 21.73 mg/dl in untreated db/db, P < 0.05) and Hb A(1c) levels (9.47 +/- 0.79% in treated db/db vs. 12.1 +/- 0.73% in untreated db/db, P +/- 0.05) but also ameliorated the increases in albuminuria and markers of glomerulosclerosis and liver injury seen in untreated db/db mice. Furthermore, both renal expressions of NF-kB p65, MCP-1, Nox4, Nox2, and p47phox and urine TBARS levels and liver productions of myeloperoxidase and reactive oxygen species, the markers of tissue inflammation and oxidative stress, were increased in untreated db/db mice, which were reduced by dapagliflozin administration. These results demonstrate that dapagliflozin not only improves hyperglycemia but also slows the progression of diabetes-associated glomerulosclerosis and liver fibrosis by improving hyperglycemia-induced tissue inflammation and oxidative stress.

• 出版日期2017-11