Thyroid hormone ameliorates diabetic nephropathy in a mouse model of type II diabetes

Abstract

Conventional therapies for diabetic patients, such as strict glycemic control, do not completely stop the progression of diabetic nephropathy. Serum-free tri-iodothyronine (T3) levels were lower in patients with type II diabetes. The purpose of this study was to test a hypothesis that treatment with T3 would improve diabetic nephropathy in db/db mice, a model of type II diabetes. Male db/db mice (16 weeks) were treated with T3 for 4 weeks. Urinary excretions of albumin and blood glucose levels were measured. Kidneys were collected for histological examination and molecular assays of transforming growth factor-β1 (TGF-β1) expression and phosphatidylinositol 3-kinase (PI3K). T3 attenuated albuminuria in db/db mice, suggesting an improved kidney function. T3 significantly decreased accumulation of collagenous components in cortical interstitium (interstitial fibrosis) and expansion of mesangial matrix in glomeruli (glomerulosclerosis) and prevented the loss of glomeruli in db/db mice. Therefore, T3 improved the renal structural damage seen in diabetic mice. Notably, diabetic nephropathy was accompanied by a significant decrease in PI3K activity and an increase in TGF-β1 expression in kidneys. T3 restored renal PI3K activity, attenuated hyperglycemia, and decreased renal TGF-β1 expression in db/db mice. These effects of T3 were abolished by simultaneous treatment with PI3K inhibitor (LY294002). These data suggest that T3 prevented progressive kidney damage and remodeling in db/db mice by improving insulin signaling (e.g. PI3K activity).