The Role And Mechanism Of GDF15 In Promoting Peritoneal Fibrosis Through Inhibition Of Cellular Autophagy

Background:Peritoneal dialysis is a form of renal replacement therapy that relies primarily on the peritoneum as a biological semi-permeable membrane for ultra filtration and solute transport.However,prolonged exposure of the peritoneum to high sugar dialysis fluid predisposes it to peritoneal fibrosis(PF),resulting in ultrafiltration failure(UF).One of the major causes of peritoneal fibrosis may be the inhibition of the autophagic pathway by high glucose,which leads to the development of peritoneal fibrosis.Peritoneal fibrosis has become the main reason why patients are unable to continue with peritoneal dialysis.Growth differentiation factor 15(GDF15)is a member of the Transforming Growth Factors-β(TGF-β)superfamily and plays an important role in liver fibrosis,cardiac fibrosis and lung fibrosis.However its regulation of peritoneal fibrosis is not yet known.Objective:The aim of this study was to investigate the role of GDF15 in peritoneal fibrosis and related mechanisms,and to provide a theoretical basis for exploring new targets for the prevention and treatment of peritoneal fibrosis.Methods.In this study,we used plasmid transfection to down-regulate or overexpress GDF 15 in rats with peritoneal fibrosis and rat primary peritoneal mesothelial cells,and used immunohistochemical technology(IHC)and Western blot to detect protein expression.The expression of mRNA was measured by Western blot,mRNA expression was measured by real-time fluorescence PCR,peritoneal fibrosis was measured by Masson,and peritoneal function was assessed by peritoneal homeostasis assay.Results:The expression of GDF15 was elevated in the rat peritoneal fibrosis model.GDF15 expression was up-and down-regulated in peritoneal tissues by microbubble transfection,and it was found that knockdown of GDF15 reduced extracellular matrix deposition,improved peritoneal function and reduced peritoneal fibrosis.In contrast,overexpression of GDF15 increased peritoneal fibrosis.TGF β1 stimulation of rat peritoneal primary mesothelial cells was used as an in vitro model,and the same results were obtained as in the in vivo experiments.Further studies revealed that GDF15 inhibited autophagy through the PI3K/Akt/mTOR signalling pathway and thus played a role in promoting peritoneal fibrosis.Conclusion:In conclusion,GDF15 is a promoter in peritoneal fibrosis and its expression promotes the development of peritoneal fibrosis.gDF 15 also inhibits autophagy through the PI3K/Akt/mTOR signaling pathway to promote peritoneal fibrosis.