PRMT1-mediated methylation of UBE2m promoting calcium oxalate crystal-induced kidney injury by inhibiting fatty acid metabolism.

Calcium oxalate (CaOx) is the most common type of kidney stone, and its crystal deposition can induce oxidative stress, inflammatory responses, and cell death. This further aggravates kidney structural and functional damage, which in turn, promotes kidney stone recurrence, forming a vicious cycle of repeated stone formation and renal injury. Therefore, identifying precise and effective therapeutic targets is crucial to prevent the damage and inflammation caused by kidney stones. Protein arginine methyltransferase 1 (PRMT1) is a well-known epigenetic regulatory enzyme involved in renal metabolic reprogramming. However, the role of PRMT1-mediated arginine methylation in kidney stone-induced renal injury remains unclear. In this study, mice with specific deletion or overexpression of PRMT1 in tubular epithelial cells were developed, and a CaOx crystal-induced kidney injury mouse model was established. Single-cell RNA-sequencing, metabolomic, proteomic, and transcriptomic analyses, together with immunoprecipitation, mass spectrometry, GST-pulldown assays, oxygen consumption rate assays, and other methods, were used to reveal the mechanism of PRMT1 in renal injury caused by CaOx crystals. Specifically, PRMT1 enhanced the protein function of UBE2m through arginine methylation at R169, and increased the neddylation level and protein stability of NEDD4, thereby inducing PPARγ ubiquitination. Increased PPARγ degradation inhibited downstream fatty acid metabolism, leading to renal lipid accumulation, disrupted energy metabolism, and impaired kidney function. These findings provide a novel potential therapeutic target for CaOx kidney stones.