SENP3 Aggravates Renal Tubular Epithelial Cell Apoptosis in Lipopolysaccharide-Induced Acute Kidney Injury via deSUMOylation of Drp1.

BACKGROUND

Sepsis causes acute kidney injury (AKI) in critically ill patients, although the mechanisms underlying the pathophysiology are not fully understood. SUMO-specific proteases 3 (SENP3), a member of the deSUMOylating enzyme family, is known as a redox sensor and could regulate multiple cellular signaling pathways. However, the role of SENP3 in septic AKI remains unclear.

OBJECTIVES

The purpose of this study was to investigate the role of SENP3 in lipopolysaccharide (LPS)-induced AKI model.

METHODS

C57BL/6 mice were given intraperitoneal injection of LPS (10 mg/kg). NRK-52E cells were treated with LPS in vitro. The SENP3 protein expression was analyzed by Western blotting. The levels of reactive oxygen species (ROS) in cells were measured using DCFH-DA. SENP3-siRNA or SENP3-plasmid was, respectively, transfected into NRK-52E cells to knock down or overexpress the SENP3 expression. Western blotting was performed to analyze the protein expression of cleaved caspase 3, cytochrome c, and dynamin-related protein 1 (Drp1). The mitochondrial membrane potential was measured using JC-1 assay kit. Co-immunoprecipitation was used to determine the interaction of Drp1 and SMUO2/3.

RESULTS

SENP3 protein expression was obviously increased in renal tissues from the mouse model of LPS-induced AKI. Accordingly, SENP3 expression was upregulated in NRK-52E cells treated with LPS in a ROS-dependent manner in vitro. Knockdown of SENP3 dramatically ameliorated LPS-induced apoptosis of NRK-52E cells, whereas overexpression of SENP3 further aggravated LPS-induced apoptosis of NRK-52E cells. Mechanistically, SENP3 triggered Drp1 recruitment to mitochondria by increasing the deSUMOylation of Drp1.

CONCLUSION

SENP3 aggravated renal tubular epithelial cell apoptosis in LPS-induced AKI via Drp1 deSUMOylation manner.