UCP2-Driven Fatty Acid Oxidation Promotes Macrophage M2 Polarization and Renal Fibrosis.

INTRODUCTION: During renal fibrosis, macrophages play a crucial role in multiple processes, such as initiating inflammation, mediating tissue repair, and promoting interstitial fibrosis. Macrophage polarization is a key determinant of their functional properties. This study aimed to investigate the roles and mechanism of macrophages with distinct phenotype in renal fibrosis. METHODS: We established unilateral ureteral obstruction and ischemia-reperfusion injury models using macrophage-specific Ucp2-KO mice induced by tamoxifen. Bone marrow-derived macrophages treated with TGF-β1 and IL-4 were used for in vitro experiments. We also employed a chimeric model via adoptive transfer of macrophages. RESULTS: We indicated that the energy metabolism pattern is a key factor during macrophage phenotypic switching. Specifically, uncoupling protein 2 (UCP2), a mitochondrial inner membrane protein, was found to regulate the metabolic profile of macrophages. Knockout of Ucp2 in macrophages led to reduced fatty acid oxidation, downregulation of M2 phenotype markers, and alleviation of renal fibrosis. Attenuation of renal interstitial fibrosis was observed in wild-type mice receiving Ucp2-deficient (Ucp2-KO) macrophages. In contrast, adoptive transfer of wild-type macrophages into Ucp2-KO mice resulted in a marked aggravation of renal fibrosis. CONCLUSION: In summary, we identified UCP2 as a key regulator of macrophage metabolic reprogramming and a critical promoter of renal fibrosis, suggesting that targeting UCP2 represents a promising therapeutic strategy.