Investigating the therapeutic effects and mechanisms of Roxadustat on peritoneal fibrosis Based on the TGF-ß/Smad pathway.

ABSTRACT

Peritoneal fibrosis (PF) is particularly common in individuals undergoing peritoneal dialysis (PD). Fibrosis of the parenchymal tissue typically progresses slowly. Therefore, preventing and reducing the advancement of fibrosis is crucial for effective patient treatment. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), primarily used to treat and improve renal anemia. Recent studies have found that HIF-1α possesses antioxidant activity and exerts a certain protective effect in ischemic heart disease and spinal cord injury, while it can also delay the progression of pulmonary and renal fibrosis. This study establishes the mice model through intraperitoneal injection of 4.25 % peritoneal dialysate fluid (PDF) and explores the therapeutic effects of Roxadustat by inducing TGF-ß1-mediated epithelial-mesenchymal transition (EMT) in Met-5A cells. The aim is to investigate the protective role and mechanisms of Roxadustat against PD-related PF. We observed thicker peritoneal tissue and reduced permeability in animals with PD-related PF samples. This was accompanied by heightened inflammation, which Roxadustat alleviated by lowering the levels of inflammatory cytokines (IL-6, TNF-α). Furthermore, Roxadustat inhibited EMT in PF mice and TGF-ß1-induced Met-5A cells, as evidenced by decreased expression of fibrotic markers, such as fibronectin, collagen I, and α-SMA, alongside an elevation in the expression of the epithelial marker, E-cadherin. Roxadustat also significantly decreased the expression of TGF-ß1 and the phosphorylation of p-Smad2 and p-Smad3. In conclusion, Roxadustat ameliorates peritoneal fibrosis through the TGF-ß/Smad pathway.