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Blocking Macrophage Migration Inhibitory Factor Protects Against Cisplatin-Induced Acute Kidney Injury in Mice.

Li, Jinhong; Tang, Ying; Tang, Patrick M K; Lv, Jun; Huang, Xiao-Ru; Carlsson-Skwirut, Christine; Da Costa, Lydie; Aspesi, Anna; Fröhlich, Suada; Szczesniak, Pawel; Lacher, Philipp; Klug, Jörg; Meinhardt, Andreas; Fingerle-Rowson, Günter; Gong, Rujun; Zheng, Zhihua; Xu, Anping; Lan, Hui-Yao.
Mol Ther; 26(10): 2523-2532, 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30077612
Macrophage migration inhibitory factor (MIF) is elevated in patients with acute kidney injury (AKI) and is suggested as a potential predictor for renal replacement therapy in AKI. In this study, we found that MIF also plays a pathogenic role and is a therapeutic target for AKI. In a cisplatin-induced AKI mouse model, elevated plasma MIF correlated with increased serum creatinine and the severity of renal inflammation and tubular necrosis, whereas deletion of MIF protected the kidney from cisplatin-induced AKI by largely improving renal functional and histological injury, and suppressing renal inflammation including upregulation of cytokines such as interleukin (IL)-1ß, tumor necrosis factor-alpha (TNF-α), IL-6, inducible nitric oxide synthase (iNOS), MCP-1, IL-8, and infiltration of macrophages, neutrophils, and T cells. We next developed a novel therapeutic strategy for AKI by blocking the endogenous MIF with an MIF inhibitor, ribosomal protein S19 (RPS19). Similar to the MIF-knockout mice, treatment with RPS19, but not the mutant RPS19, suppressed cisplatin-induced AKI. Mechanistically, we found that both genetic knockout and pharmacological inhibition of MIF protected against AKI by inactivating the CD74-nuclear factor κB (NF-κB) signaling. In conclusion, MIF is pathogenic in cisplatin-induced AKI. Targeting MIF with an MIF inhibitor RPS19 could be a promising therapeutic potential for AKI.
Selo DaSilva