Agomelatine, a structural analog of melatonin, improves kidney dysfunction through regulating the AMPK/mTOR signaling pathway to promote autophagy in obese rats

Abstract

This study aimed to investigate the renoprotective effect of agomelatine on kidney injury in an obese rat model and to understand the underlying mechanisms involving the AMPK-mTOR-autophagy signaling pathway. Male Wistar rats were fed either a normal (ND) or a high-fat diet (HF) for 16 weeks. The HF rats were divided into 4 groups: (1) HF control; (2) AGOM20 receiving agomelatine 20 mg. kg−1 day−1; (3) AGOM40 receiving agomelatine 40 mg. kg−1 day−1; and (4) NAC receiving N-acetylcysteine 100 mg. kg−1 day−1 by oral gavage for 4 weeks. HF rats demonstrated insulin resistance, impaired renal function and oxidative stress as evidenced by the elevation of MDA levels and expression of PKCα and NOX4. These alterations correlated with impaired autophagy, renal fibrosis and apoptosis. Agomelatine showed a greater efficacy than NAC treatment with regard to improving insulin resistance, dyslipidemia and renal dysfunction through alleviation of oxidative stress, fibrosis and apoptosis in kidney cells. Impaired autophagy was blunted after agomelatine or NAC administration, as demonstrated by the increased in Beclin-1, LC3B, Atg5, LAMP2, and AMPK, and decreased mTOR and CTSB expression. These data revealed that agomelatine protected against obesity-induced kidney injury via the regulation of ROS and AMPK-mTOR-autophagy signaling pathways.