5 years ago

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

Tian, Wu, Smith, Johansson, Peng, Sjostrom, Huang, Tang
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 18week-old uninephrectomized db/db mice with a selective SGLT2 inhibitor dapagliflozin. Untreated db/db mice developed progressive albuminuria, glomerular mesangial matrix expansion and fatty liver, associated with increased renal expression of TGFß1, PAI-1, type IV collagen and fibronectin and liver deposition of fibronectin, type I & III collagen and laminin. Treatment with dapagliflozin (1mg/kg/d) via gel diet from 18 to 22 weeks 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 HbA1c 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. Further, both renal expressions of NF-kBp65, 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.

Publisher URL: http://doi.org/10.1152/ajpendo.00086.2017

DOI: 10.1152/ajpendo.00086.2017

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