Melanocortin 1 Receptor Signaling Protects Against Tubular Epithelial Cell Injury and M1 Macrophage Polarization in Acute Kidney Injury

Acute kidney injury (AKI) is characterized by high incidence and mortality rates, and a lack of specific targeted therapies. Inflammatory responses mediated by immune cells and direct damage to renal tubular epithelial cells underlie AKI development. Melanocortin exerts renoprotective effects through systemic immune regulation; however, the renoprotective role of melanocortin 1 receptor (MC1R) remains unclear. MC1R-deficient (e/e) mice developed higher serum creatinine levels, more severe renal dysfunction, and greater histological damage than wild-type (WT) mice following folic acid-induced AKI. Treatment with MC1R agonist MS05 improved experimental nephritis in WT mice; however, this effect was less pronounced in e/e mice. The exacerbation of AKI in e/e mice was associated with damage to renal tubular epithelial cells and macrophage infiltration, where MC1R is highly expressed. MC1R alleviates tubular cell inflammation by inhibiting the nuclear factor-κB pathway and suppresses the polarization of M1 macrophages. Chimeric mice were generated through transplantation of bone marrow-derived macrophages after irradiation. Macrophages from e/e mice with MC1R dysfunction exacerbated kidney injury in WT mice, whereas those from WT mice mitigated kidney injury in e/e mice. Targeting MC1R in renal tubular epithelial cells and macrophages provides a novel treatment concept for AKI.