Agomelatine Ameliorates Obesity-Induced Kidney Injury through the Inhibition of Renal Fibrosis and Improvement of Impaired Autophagy

Abstract

INTRODUCTION: Chronic kidney disease is the crucial complication that could occur in obesity. Prolong high-fat diet consumption can stimulate reactive oxygen species (ROS) and contribute to kidney injury through various pathways. Autophagy plays an important role for maintaining intracellular homeostasis. ROS could induce impaired autophagy, subsequently led to kidney damage. Agomelatine (AGOM), a melatonin analogue, is indicated for the treatment of major depressive disorders. The antioxidant and anti-inflammation effects have been reported in AGOM treatment in chronic mild stress-induced depression. Previous study found that AGOM inhibited apoptosis and ER stress in the kidney under high-fat diet condition in rats. However, the effect of AGOM supplementation on renal fibrosis and impaired autophagy in obese condition has never been elucidated. AIMS: To evaluate the renoprotective effect of AGOM on kidney function in high-fat diet-induced kidney injury, as well as to explore the underlying mechanisms involving autophagy signaling pathway. MATERIALS AND METHODS: Male Wistar rats were received normal diet (ND) or high-fat diet (HF) for 16 weeks. Then, the HF rats were separated into 4 subgroups including (1) HF; (2) agomelatine20 (AGOM20); (3) AGOM40, the rats were received AGOM at the dose of 20 and 40 mg/kg/day, respectively; and (4) N-acetylcysteine (NAC), the rats were received NAC at the dose of 100 mg/kg/day by oral gavage for 4 weeks. After 4 weeks of treatment, all rats were sacrificed. Blood, urine and kidney tissues were collected for further investigations. RESULTS: The results demonstrated that HF rats developed kidney dysfunction as shown by the raising in serum creatinine, creatinine clearance along with the changes of glomerular structure and the elevating of positive area of α-SMA, which is renal fibrosis indicator. These alterations were reversed by AGOM and NAC treatment. Moreover, HF rats showed renal oxidative stress as indicated by the increasing in PKCα and NOX4 expression and decreasing in antioxidant enzyme, GCLC. AGOM and NAC administrations reduced oxidative stress and restored antioxidant enzyme. Furthermore, high-fat diet consumption markedly reduced AMPK, along with the elevation of mTOR expression. Additionally, we found that HF rats aggravated impaired autophagy which could induce oxidative stress, fibrosis and finally led to kidney cell death. AGOM administration restored autophagy process as shown by the increasing in Beclin-1, LC3B and Atg5 protein. These results demonstrated that AGOM improved kidney injury through the regulation of oxidative stress, fibrosis and autophagy process. CONCLUSIONS: These findings indicated that AGOM prevented kidney injury under obese condition via the inhibition of oxidative stress and fibrosis and improved impaired autophagy via regulating AMPK-mTOR-autophagy signaling pathways.