Deficiency of IKK α in Macrophages Mitigates Fibrosis Progression in the Kidney after Renal Ischemia-Reperfusion Injury.

Aims . Acute kidney injury (AKI) can lead to chronic kidney disease (CKD), and macrophages play a key role in this process. The aim of this study was to discover the role of I κ B kinase α (IKK α ) in macrophages in the process of AKI-to-CKD transition. Main Methods . We crossed lyz2-Cre mice with IKK α -floxed mice to generate mice with IKK α ablation in macrophages (Mac IKK α -/-). A mouse renal ischemia/reperfusion injury (IRI) model was induced by clamping the renal artery for 45 minutes. Treated mice were evaluated for blood biochemistry, tissue histopathology, and fibrosis markers. Macrophages were isolated from the peritoneal cavity for coculturing with tubular epithelial cells (TECs) and flow cytometry analysis. Key Findings . We found that fibrosis and kidney function loss after IRI were significantly alleviated in Mac IKK α -/- mice compared with wild-type (WT) mice. The expression of fibrosis markers and the infiltration of M2 macrophages were decreased in the kidneys of Mac IKK α -/- mice after IRI. The in vitro experiment showed that the IRI TECs cocultured with IKK α -/- macrophages (KO M Φ s) downregulated the fibrosis markers accompanied by a downregulation of Wnt/ β -catenin signaling. Significance . These data support the hypothesis that IKK α is involved in mediating macrophage polarization and increasing the expression of fibrosis-promoting inflammatory factors in macrophages. Therefore, knockdown of IKK α in macrophages may be a potential method that can be used to alleviate the AKI-to-CKD transition after IRI.