USP18 reduces the inflammatory response of LPS-induced SA-AKI by inhibiting the PI3K-AKT-NF-κB pathway and regulate apoptosis of cells

Author:

Chong Yang1ORCID,Wu Xue-ying2,Wang Yi-qi1,Gu Quan-kuan1,Zhang Jian-nan1,Meng Xiang-lin1,Li Yue1,Yang Wei1,Li Na-na1,Liu Huan-huan1,Gao Qian-qian1,Zhao Ming-yan1

Affiliation:

1. Department of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China

2. Department of General Medicine, Harbin First Hospital. Harbin, China

Abstract

Background Sepsis-associated acute kidney injury (SA-AKI) is marked by systemic inflammation and organ dysfunction. Ubiquitin-specific protease 18 (USP18) is a regulator in immune responses and apoptosis. Objectives To explore USP18's role in inflammatory pathways and apoptosis in SA-AKI, particularly its interactions with the PI3K-AKT-NF-κB pathway. Design A combination of animal experiments and cellular models was employed to investigate the expression and regulatory functions of USP18 in both in vivo and in vitro settings. Methods We established SA-AKI models in mice and HK-2 cells using LPS. Gene expression was analyzed via RNA-seq, and Cr, BUN, and inflammatory factors were measured using biochemical assays and ELISA. Kidney pathology was assessed with HE staining, mRNA levels with qRT-PCR, protein expression with Western blots, and cell apoptosis with flow cytometry. Results In SA-AKI mice model and HK-2 cell lines, upregulated USP18 was linked to increased activity in the PI3K-AKT-NF-κB pathway and heightened inflammation. Conversely, USP18 downregulation decreased early cell apoptosis and raised levels of inflammatory proteins. Elevated USP18 levels were also found in SA-AKI patients’ blood and urine. Conclusion USP18 enhances in vitro and in vivo responses by modulating inflammation and apoptosis through the PI3K-AKT-NF-κB pathway, presenting a potential target for SA-AKI therapy.

Funder

National Natural Science Foundation of China

Heilongjiang Province Key R&D Program

The experiments were done in Heilongjiang Province Key Laboratory of Critical Care Medicine

Publisher

SAGE Publications

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