Sigma-1 Receptor Rescues Autophagy Through AMPK/mTOR Signaling Pathway in Sepsis-Induced Acute Kidney Injury

Wei Jiang,1 Jianfeng Zhang,2 Yinan Zhang,3 Zhongwei Huang1 1Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China; 2Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China; 3Department of Dermatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of ChinaCorrespondence: Zhongwei Huang, Department of Emergency Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu, 226001, People’s Republic of China, Email [email protected]: This study aimed to investigate the effects of σ-1R on autophagy in sepsis-AKI and its potential involvement in the AMPK/mTOR signaling pathway.Methods: The serum samples from patients were used to diagnose sepsis and sepsis-AKI using double-blind and randomized method and to quantify σ-1R and inflammatory cytokines using enzyme-linked immunosorbent assays. HK-2 cells induced by lipopolysaccharide (LPS) were employed as an in vitro model of sepsis-AKI. To evaluate the function of σ-1R in sepsis-AKI, siRNA and an overexpression plasmid targeting σ-1R were used. σ-1R and autophagy marker expressions were analyzed using quantitative real-time polymerase chain reaction and Western blot assays. Cell proliferation was evaluated using CCK-8 and EdU assays, and cell apoptosis was detected using flow cytometry and TUNEL staining assays. Phosphorylated proteins were detected in the AMPK/mTOR signaling pathway.Results: In sepsis and sepsis-AKI, σ-1R levels were reduced, whereas the levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) increased. σ-1R promoted the proliferation of LPS-induced HK-2 cells while inhibiting apoptosis. Moreover, σ-1R enhanced autophagy, as evidenced by the upregulation of autophagy biomarkers LC3-II/LC3-I and Beclin 1. Furthermore, σ-1R promoted the phosphorylation of AMPK and ULK1 while inhibiting mTOR.Conclusion: σ-1R utilizes the AMPK/mTOR signaling pathway to enhance autophagy in sepsis-AKI, indicating that σ-1R may serve as a promising target for sepsis-AKI diagnosis and therapy.Keywords: sepsis-induced acute kidney injury, sigma-1 receptor, autophagy, AMPK/mTOR signaling pathway