Empagliflozin improves renal ischemia–reperfusion injury by reducing inflammation and enhancing mitochondrial fusion through AMPK–OPA1 pathway promotion

作者：Wenbo Yang, Xiaoli Li, Liujie He, Shuyang Zhu, Shicong Lai, Xiaopeng Zhang, Zixiong Huang, Biyue Yu, Chun‐Ping Cui, Qiang Wang · 发表于：Cellular & Molecular Biology Letters · 年份：2023 · DOI：10.1186/s11658-023-00457-6 · 被引用次数：55 · 研究领域：Mitochondrial Function and Pathology、Metabolism and Genetic Disorders、Acute Kidney Injury Research

BACKGROUND: Renal ischemia-reperfusion injury (IRI) is one reason for renal transplantation failure. Recent studies have shown that mitochondrial dynamics is closely related to IRI, and that inhibition or reversal of mitochondrial division protects organs against IRI. Optic atrophy protein 1 (OPA1), an important factor in mitochondrial fusion, has been shown to be upregulated by sodium-glucose cotransporter 2 inhibitor (SGLT2i). Also, the antiinflammatory effects of SGLT2i have been demonstrated in renal cells. Thus, we hypothesized that empagliflozin could prevent IRI through inhibiting mitochondrial division and reducing inflammation. METHODS: Using hematoxylin-eosin staining, enzyme linked immunosorbent assay (ELISA), flow cytometry, immunofluorescent staining, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining, real-time PCR, RNA-sequencing, and western blot, we analyzed renal tubular tissue from in vivo and in vitro experiments. RESULTS: Through animal experiments and sequencing analysis, we first confirmed the protection against IRI and the regulation of mitochondrial dynamics-related factors and inflammatory factors by empagliflozin pretreatment. Then, through hypoxia/reoxygenation (H/R) cellular experiments, we confirmed that empagliflozin could inhibit mitochondrial shortening and division and upregulate OPA1 in human renal tubular epithelial cell line (HK-2) cells. Subsequently, we knocked down OPA1, and mitochondrial divisi...