Nur77 Promotes Inflammation in Cisplatin-Induced Acute Kidney Injury Through Transactivation of SERPINA3 Mediating Wnt/β-Catenin Pathway

Aim: Acute kidney injury (AKI) is the most common complication in the treatment of cisplatin, which is a clinically effective and classical Anticancer drug. Orphan Nuclear Receptor Nur77 has been found to promote renal ischaemia-reperfusion injury. In this study, we aim to explore the effects of Nur77 on cisplatin-induced AKI (CI-AKI) and its underlying mechanism.

Methods: HK-2 cells treated with cisplatin were used to construct the CI-AKI model in vitro. Cell viability and cell proliferation were analysed using CCK-8 and EdU assays, respectively. Cell Apoptosis was analysed by flow cytometry. The inflammation release level was detected using ELISA. Molecular abundance was evaluated using qPCR, Western blot and immunofluorescence. The interaction between Nur77 and SERPINA3 was clarified using ChIP and dual-luciferase reporter gene assays.

Results: Our works demonstrated that Nur77 and SERPINA3 expression were considerably ascended in cisplatin-induced HK-2 cells. The silence of SERPINA3 alleviated cisplatin-stimulated HK-2 cell injury, which was characterised by increased cell viability and proliferation, and decreased Apoptosis and inflammatory cytokine release. In addition, Nur77 promotes SERPINA3 transcription by binding to the SERPINA3 promoter region (-182 to -175), thereby upregulating SERPINA3 expression and activating the Wnt/β-catenin pathway. Moreover, HK-2 cell injury induced by cisplatin was notably inhibited by the knockdown of Nur77. Furthermore, the efficacy of Nur77 downregulation on the cell injury in cisplatin-stimulated HK-2 cells was antagonised by SERPINA3 overexpression.

Conclusion: Taken together, our findings revealed that Nur77 knockdown resisted cisplatin-induced HK-2 cells injury through lessening the expression of SERPINA3 mediated by transcriptional regulation and inactivating the Wnt/β-catenin pathway.

Wnt/β‐catenin pathway; acute kidney injury; cisplatin; orphan nuclear receptor Nur77; serine protease inhibitor clade A member 3.