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 (T 3 ) levels were lower in patients with type II diabetes. The purpose of this study was to test a hypothesis that treatment with T 3 would improve diabetic nephropathy in db/db mice, a model of type II diabetes. Male db/db mice (16 weeks) were treated with T 3 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-b1 (TGF-b1) expression and phosphatidylinositol 3-kinase (PI3K). T 3 attenuated albuminuria in db/db mice, suggesting an improved kidney function. T 3 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, T 3 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-b1 expression in kidneys. T 3 restored renal PI3K activity, attenuated hyperglycemia, and decreased renal TGF-b1 expression in db/db mice. These effects of T 3 were abolished by simultaneous treatment with PI3K inhibitor (LY294002). These data suggest that T 3 prevented progressive kidney damage and remodeling in db/db mice by improving insulin signaling (e.g. PI3K activity).

Thyroid hormones and diabetic nephropathy: An essential relationship to recognize

“…And thyroid hormones can affect insulin signalling indirectly through affecting tyrosine phosphorylation of insulin receptor substrate and activation of phosphoinositide 3‐ kinase, serum FT3 levels are associated with insulin secretion . Furthermore, thyroid hormones and thyroid hormone receptors may play important roles in modulating the inflammatory response, and interactions have been demonstrated among inflammation, oxidative stress, and thyroid dysfunction …”

“…A recent cohort study by Shin et al showed that thyroid hormone replacement therapy not only preserved renal function, but was also an independent predictor of renal outcome in CKD patients with SCH. It had been reported that triiodothyronine restored renal phosphatidylinositide 3‐kinase activity and decreased renal transforming growth factor‐β1 expression in db/db mice, similar to the function of insulin . It is therefore important to screen and detect thyroid hormones changes in DN patients, especially those with SCH and/or low‐FT3.…”

“…Additionally, Aziz suggested that thyroxine replacement therapy was essential for controlling microalbuminuria, spot urine protein, and blood pressure in diabetic patients with CKD and hypothyroidism. One recent study in db/db mice of T2 DM noted that thyroid hormone could interfere with accumulation of collagenous components in cortical interstitium and glomerular mesangial matrix by impacting TGF‐β1 expression and regulate renal structure . Similarly, diabetic patients with higher thyroid stimulating hormone (TSH) and lower FT3 levels were more likely to develop DN, and SCH was shown to be an independent risk factor for the progression of DN .…”

Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses

“…Thus, it has been reported that hypothyroidism induced by antithyroidal drugs can prevent pulmonary and cutaneous fibrosis induced by hypochlorous acid (51) and to improve survival after acute thioacetamide administration in the rat (52). However, hypothyroidism also induces cardiac fibrosis in the rat (53,54), thyroid hormone administration ameliorates kidney fibrosis (55), and thyroid disfunction and subclinical hypothyroidism have been associated with primary biliary cirrhosis, primary sclerosing cholangitis, and nonalcoholic fatty liver disease in humans (29,32). These observations reveal the complex role of the thyroid hormones on fibrosis that could depend on the type of insult or tissue examined.…”

The Impact of TSH Level on Albuminuria and Glomerular Filtration Rate in Type 2 Diabetes Mellitus.

“…A mouse model done in 2011 seemed promising. [23] 1236 Levothyroxine replacement was shown to preserve renal functions and independently predict renal outcome in 309 patients with stage 2-4 chronic kidney disease and SCH. [24] Another study showed that thyroid replacement therapy may slow down the deterioration of eGFR in a cohort of patients, 39% of which had diabetes mellitus.…”