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

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).