GLP-1 Alleviates Diabetic Kidney Disease Through Activation of Autophagy by Regulating AMPK/mTOR Pathway.

Yang, Shuangli; Lin, Chuman; Zhuo, Xiaoyun; Wang, Jiyu; Rao, Shitao; Xu, Wen; Cheng, Yanzhen; Yang, Li

Glucagon-like peptide-1 (GLP-1) is a novel anti-diabetic agent used in clinical practice. Recently, it was reported to exert a renoprotective effect in the HK-2 cells and kidneys of diabetic rats, which was induced by one type of GLP-1 analogues liraglutide in the presence of high glucose. However, most of the previous findings mainly focused on its indirect effect in inhibiting the advanced glycation end products. Here, besides glycemic control, we also demonstrated a stimulatory role of liraglutide in promoting autophagy and relieving oxidative stress in Zucker diabetic fatty(ZDF) rats. The renoprotective effect of liraglutide has been demonstrated by significantly decreasing urinary albumin (P<0.01) and ameliorating renal pathological changes (P<0.001) in vivo. Besides that, proliferation of Hkc8 and HEK293 cells have been increased after treating with exendin-4, a GLP-1 receptor agonist. Moreover, the GLP-1 could positively improve the progression of autophagy in vivo and in vitro through regulating the autophagy-related protein LC3 and P62 via AMPK/mTOR signaling pathway. Simultaneously, it could reverse Nrf2 translocation into the nuclei, then suppress oxidative stress. In terms of mechanism, the renoprotective effect of the GLP-1 would be exerted via the GLP1R-AMPK-mTOR-autophagy-ROS signaling axis. The present study not only illustrates the renoprotective effect of the GLP-1 in DKD rats but also in the first time elucidates the underlying mechanism that is independent of controlling glucose, which implies that the GLP-1 might be a novel therapeutic strategy for the prevention and treatment of DKD.