WIP1-mediated regulation of p38 MAPK signaling attenuates pyroptosis in sepsis-associated acute kidney injury

• Published in: Immunobiology (1979) 2024-09, Vol.229 (5), p.152832, Article 152832
• Main Authors: Wang, Yinhong, Cui, Chenkai, Zhao, Weihao, Tian, Xuefei, Liu, Pengfei, Wei, Linting, Zhu, Zikun, Liu, Ming, Fu, Rongguo, Jia, Lining
• Format: Article
• Language: English
• Subjects: Acute kidney injury; Acute Kidney Injury - etiology; Acute Kidney Injury - metabolism; Animals; Cell Line; Disease Models, Animal; Humans; Lipopolysaccharides; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; NLRP3; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; Protein Phosphatase 2C - metabolism; Pyroptosis; Sepsis - complications; Sepsis - metabolism; Signal Transduction; WIP1
• ISSN: 0171-2985; 1878-3279; 1878-3279
• DOI: 10.1016/j.imbio.2024.152832

[Display omitted] Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) is a serine/threonine phosphatase that plays a significant role in various physiological processes. However, the involvement of WIP1 in kidney remains unclear. Lipopolysaccharide (LPS) was administered to induce acute injury in mice and human kidney 2 (HK2) cells in the study. The WIP1 inhibitor, CCT007093, was administered both in vitro and in vivo to assess its effect on kidney. The single-cell sequencing (scRNA-seq) data revealed that Ppm1d mRNA reached peak on day 2 following unilateral ischemia–reperfusion injury (uni-IRI) in mice, especially in the proximal renal tubules during repair phase. Compared to the control group, WIP1 protein exhibited a significant increase in renal tubules of patients with acute tubular injury (ATI) and mice with LPS-induced acute kidney injury (AKI), as well as in LPS-injured HK2 cells. In vitro experiments showed that CCT007093 increased the protein levels of NLRP3, cleaved-Caspase1, GSDMD-N and IL-1β in HK2 cells and further reduced the viability of LPS-stimulated HK2 cells. In vivo experiments showed that inhibition of WIP1 activity with CCT007093 further increased cleaved-Caspase1, GSDMD-N protein levels in kidney tissue from mice with LPS-induced AKI. In addition, LPS induces phosphorylation of p38 MAPK, a key regulator of pyroptosis, which is further activated by CCT007093. In conclusion, inhibition of WIP1 activity acts as a positive regulator of renal tubular pyroptosis mainly through the mediation of phospho-p38 MAPK.