MECHANISM OF MICRORNA-218-5P IN MITOCHONDRIAL BIOGENESIS OF SEPSIS-INDUCED ACUTE KIDNEY INJURY BY THE REGULATION OF PGC-1Α

Abstract

ABSTRACT Background: Sepsis-induced acute kidney injury (SI-AKI) is a kind of kidney dysfunction, which brings a lot of suffering. This study aimed to figure out the role of the miR-218-5p/PGC-1α axis in SI-AKI. Methods: AKI mouse model was established through cecal ligation and puncture. PGC-1α expression was activated using an activator ZLN005 before the serum and tissue samples were collected. Next, pathological structure and apoptosis of kidney tissues were observed. Levels of blood urea nitrogen, serum creatinine, and indicators of inflammation and oxidative stress were assessed. Moreover, reactive oxygen species and mitochondrial membrane potential levels, adenosine 5′-triphosphate content, and mitochondrial ultrastructure of kidney tissues were observed. HK2 cells were treated by lipopolysaccharide (LPS) to mimic sepsis in vitro, followed by evaluation of cell survival and apoptosis, inflammation, and oxidative stress. Subsequently, the binding relation between PGC-1α and miR-218-5p was predicted and validated. Then expression of PGC-1α and miR-218-5p was detected. PGC-1α and miR-218-5p expression were intervened to detect their influences in mitochondrial biogenesis. At last, miR-218-5p was overexpressed in ZLN005 (PGC-1α activating agent) pretreated SI-AKI mice to validate the mechanism. Results: PGC-1α is poorly expressed in SI-AKI, but overexpression of PGC-1α using ZLN005 alleviated SI-AKI injury and promoted mitochondrial biogenesis in AKI mice, and relieved LPS-induced cell injury. PGC-1α is a target of miR-218-5p. Downregulation of miR-218-5p expression in HK2 cells attenuated mitochondrial biogenesis disorder. Inhibition of PGC-1α annulled the role of miR-218-5p silencing in cells. In vivo, miR-218-5p overexpression partly reversed the protective role of ZLN005 in SI-AKI mice. Conclusion: miR-218-5p targeted PGC-1α to disrupt mitochondrial biogenesis, thereby exacerbating SI-AKI.