Melatonin Ameliorates Renal Fibrosis Through the Inhibition of NF-κB and TGF-β1/Smad3 Pathways in db/db Diabetic Mice

Objective. To investigate the effects and molecular mechanism of melatonin (MT) on NF-kappa B and TGF-beta/Smad3 signaling pathways in db/db diabetic mice. Methods. db/db diabetic mice were divided into five groups treated with melatonin at doses of 50,100, 200 mu g/kg, the urinary concentration was detected by ELISA, renal histology was observed in PAS paining. Mouse mesangial cells were divided into mannitol control group, normal control group, normal control + MT group, high glucose group, high glucose + different concentrations (10, 100, 1000) mmol/L MT group. The proliferation of mesangial cells was detected by EdU kit; the expression of NF-kappa Bp65, ColIV and Fn were detected by laser confocal system; the concentrations and mRNA levels of ColIV and Fn were detected by ELISA and qRT-PCR. the expressions of ColIV, Fn, I kappa B, p-I kappa B, TGF-beta 1, Smad3 and p-Smad3 were detected by Western blot in renal tissues and mesangial cells. Results. MT treatment could markedly improve the kidney histopathologic lesions. Compared with the db/m mice, 24 h urinary albumin excretion rate (UAER) and the expressions of ColIV, Fn, p-I kappa B/I kappa B, NF-kappa Bp65, TGF-beta 1 and p-Smad3/Smad3 were decreased after melatonin treatment (p < 0.05). Compared with the control group, the proliferation function of mesangial cells in high glucose group was significantly enhanced, and the expressions of ColIV, Fn, p-I kappa B/I kappa B, NF-kappa Bp65, TGF-beta 1 and p-Smad3/Smad3 in mesangial cells were significantly up-regulated (p < 0.05), and these changes were significantly lowered in MT treatment. Conclusion. Melatonin can inhibit renal inflammation and fibrosis by inhibiting the NF kappa B and TGF-beta 1/Smad3 signaling pathways, and melatonin may be a promising therapeutic target in diabetic nephropathy. (C) 2020 IMSS. Published by Elsevier Inc.