High-fat diet triggers chemerin-dependent immune reprogramming that exacerbates acute kidney injury

Obesity presents a known risk factor for acute kidney injury (AKI), but the precise mechanism underlying this phenomenon remains incompletely elucidated. In this study, we demonstrated that short-term high-fat diet (HFD) feeding aggravated kidney injury in AKI mice. Through multi-omics analysis, we identified chemerin (encoded by Rarres2) as a distinctive renal injury-related adipokine enriched in AKI tubular epithelial cells (TECs), particularly following exposure to HFD. Elevated chemerin levels were confirmed in the serum and kidney biopsy samples of AKI patients with obesity, exhibiting a negative correlation with renal function. Rarres2-/- mice were protected from HFD-induced vulnerability toward AKI as well as different types of AKI after standard diet, emphasizing its direct effect on AKI independent of metabolic factors. Mechanism investigation showed the receptor of chemerin-chemerin chemokine-like receptor 1 (CMKLR1) was expressed on renal mononuclear phagocytic cells (MPCs). By single-cell RNA sequencing (scRNA-seq) analysis, unique Cmklr1hi clusters were identified in renal MPCs following AKI, exhibiting enhanced chemotaxis and pro-inflammatory capacity. Functionally, chemerin acted as a chemoattractant to enhance the chemotaxis of Cmklr1hi MPCs. Finally, supplementation of MPCs-derived cytokines reversed kidney injury in Rarres2-/- mice confirming the role of chemerin-CMKLR1 axis in promoting inflammation and kidney damage. Collectively, we identified chemerin as a specific inflammatory and metabolic target that functions through potent pro-inflammatory Cmklr1hi macrophages. Our study suggests that targeting the chemerin-CMKLR1 axis could be a promising therapeutic strategy for AKI patients, especially those with metabolic syndrome.