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CMKLR1 as a Therapeutic Target: Vitamin D-Mediated Suppression of Inflammation and Oxidative Stress in SA-AKI

Year: 2025

Type: article

Abstract: Sepsis-associated acute kidney injury (SA-AKI) is a severe complication of sepsis, primarily driven by immune–inflammatory dysregulation and oxidative stress, and 1,25-Dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) shows renoprotective potential, yet its molecular targets and mechanisms remain unclear. Transcriptomic data of SA-AKI from GEO were analyzed by ssGSEA for immune infiltration, differential expression analysis, WGCNA, and machine learning (LASSO, SVM-RFE, Random Forest) to identify the biomarkers. In vivo, SA-AKI was induced by cecal ligation and puncture (CLP) in mice treated with 1,25(OH) 2 D 3, and renal function, histology, inflammatory cytokines, oxidative stress markers, and CMKLR1 expression were evaluated. In vitro, LPS-stimulated HK-2 cells were treated with 1,25(OH) 2 D 3 with or without CMKLR1 overexpression to assess cytokines, cell viability, apoptosis, and oxidative stress. Four key biomarkers-CMKLR1, COL1A1, RPS19, and THBS1—were identified by machine learning, with CMKLR1 as the key target. In SA-AKI mice, 1,25(OH) 2 D 3 downregulated CMKLR1, improved renal function, and reduced inflammation and oxidative stress. In LPS-stimulated HK-2 cells, it dose-dependently suppressed cytokine release, restored cell viability, and alleviated oxidative stress, while CMKLR1 overexpression partially reversed these effects. CMKLR1 was identified as a key immune inflammation target in SA-AKI. 1,25(OH) 2 D 3 was protected against renal injury by suppressing CMKLR1, and mitigating inflammation, oxidative stress, and apoptosis, while CMKLR1 overexpression partially reversed these effects. These findings highlight CMKLR1 as a potential therapeutic target for SA-AKI.

Source: Molecular Biotechnology

DOI: 10.1007/s12033-025-01534-1