The novel potential therapeutic target PSMP/MSMP promotes acute kidney injury via CCR2

• Published in: Molecular therapy Vol. 32; no. 7; pp. 2248 - 2263
• Main Authors: Song, Zhanming, Yao, Weijian, Wang, Xuekang, Mo, Yaqian, Liu, Zhongtian, Li, Qingqing, Jiang, Lei, Wang, Hui, He, Huiying, Li, Ning, Zhang, Zhaohuai, Lv, Ping, Zhang, Yu, Yang, Li, Wang, Ying
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.07.2024
• Subjects: acute kidney injury; anti-PSMP antibody; CCR2; inflammation; macrophages; macrophages; acute kidney injury; inflammation; anti-PSMP antibody; CCR2
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2024.05.028

Acute kidney injury (AKI) is a major worldwide health concern that currently lacks effective medical treatments. PSMP is a damage-induced chemotactic cytokine that acts as a ligand of CCR2 and has an unknown role in AKI. We have observed a significant increase in PSMP levels in the renal tissue, urine, and plasma of patients with AKI. PSMP deficiency improved kidney function and decreased tubular damage and inflammation in AKI mouse models induced by kidney ischemia-reperfusion injury, glycerol, and cisplatin. Single-cell RNA sequencing analysis revealed that Ly6Chi or F4/80lo infiltrated macrophages (IMs) were a major group of proinflammatory macrophages with strong CCR2 expression in AKI. We observed that PSMP deficiency decreased CCR2+Ly6Chi or F4/80lo IMs and inhibited M1 polarization in the AKI mouse model. Moreover, overexpressed human PSMP in the mouse kidney could reverse the attenuation of kidney injury in a CCR2-dependent manner, and this effect could be achieved without CCL2 involvement. Extracellular PSMP played a crucial role, and treatment with a PSMP-neutralizing antibody significantly reduced kidney injury in vivo. Therefore, PSMP might be a therapeutic target for AKI, and its antibody is a promising therapeutic drug for the treatment of AKI. [Display omitted] Wang, Yang and colleagues reveal that PSMP, a damage-induced chemotactic cytokine, is upregulated in patients with AKI and promotes AKI in mice through CCR2-dependent inflammation. PSMP deficiency and treatment with the PSMP-neutralizing antibody 3D5 significantly alleviate AKI in mice, suggesting that PSMP is a promising therapeutic target for AKI.