SMN haploinsufficiency exacerbates high glucose dialysate-induced peritoneal inflammation and fibrosis via mTOR/NFκB signaling pathway.

Peritoneal dialysis (PD) is a renal replacement therapy for patients with end-stage renal disease (ESRD). However, long-term PD treatment frequently triggers peritoneal inflammation and mesothelial-to-mesenchymal (MMT), ultimately leading to irreversible peritoneal fibrosis. In this study, a high glucose-induced peritoneal fibrosis mouse model was successfully established by intraperitoneal injection of a high-glucose (HG) peritoneal dialysate. In vitro experiments of HG-induced peritoneal fibrosis were further performed using HMrSV5 human peritoneal mesothelial cells. Exposure of Survival of motor neuron (SMN)+/- mice to PD dialysate markedly exacerbated MMT progression, increased peritoneal membrane thickness, altered peritoneal permeability, and upregulated the expression levels of proinflammatory cytokines. Administration of the mammalian target of rapamycin (mTOR) inhibitor rapamycin alleviated PD fluid-induced MMT and peritoneal fibrosis in SMN+/- mice. In vitro, SMN overexpression suppressed MMT, inflammatory response, and mTOR phosphorylation in mesothelial cells under high glucose conditions. Conversely, SMN knockdown promoted MMT, accompanied by enhanced phosphorylation of mTOR and the NFκB subunit p65. Moreover, mTOR activation reversed the inhibitory effect of SMN overexpression on NF-κB phosphorylation under high glucose conditions. Taken together, our results demonstrate that SMN haploinsufficiency aggravates high glucose-induced peritoneal inflammatory, MMT and fibrosis via the mTOR/NF-κB signaling axis. Furthermore SMN overexpression mitigates peritoneal inflammatory injury and fibrotic progression by restraining mTOR/NF-κB activation in peritoneal mesothelial cells.