The protective role of nicotinamide N-methyltransferase and its metabolite 1-methylnicotinamide in peritoneal fibrosis

BackgroundLong-term exposure to bioincompatible peritoneal dialysis (PD) solutions can cause peritoneal fibrosis (PF) and progressive loss of peritoneal membrane function. This study investigated the effects of nicotinamide N-methyltransferase (NNMT) and its metabolite 1-methylnicotinamide (MNAM) in experimental PF and examined their association with Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) expression.MethodsA rat model of PF was established using high-glucose PD fluid combined with lipopolysaccharide, and primary rat peritoneal mesothelial cells (RPMCs) were stimulated with transforming growth factor-β1 (TGF-β1). The effects of NNMT overexpression and exogenous MNAM administration were evaluated using peritoneal equilibration testing, histological analysis, quantitative real-time polymerase chain reaction, and western blot analysis.ResultsNNMT expression was decreased in TGF-β1-stimulated RPMCs and fibrotic rat peritoneal tissues. NNMT overexpression reduced fibrosis-related marker expression in RPMCs and attenuated peritoneal thickening, extracellular matrix deposition, and functional alterations in PF rats. Exogenous MNAM administration also reduced fibrotic changes and partially improved peritoneal transport parameters in PF rats. NNMT overexpression was accompanied by increased cGAS and STING expression in both models; however, pathway activity and functional involvement were not directly examined.ConclusionNNMT and MNAM exert protective effects in experimental PF. The association between NNMT overexpression and altered cGAS and STING expression requires further mechanistic investigation. The NNMT/MNAM metabolic axis may represent a potential therapeutic target for PF.