Investigation of the treatment effectiveness of TRPC ion channel family expressions and TRPC6 inhibition in a mouse liver fibrosis model

Liver fibrosis is a pathological condition characterized by fibrotic tissue formation as a result of excessive accumulation of extracellular matrix (ESM) components such as collagen in the liver in response to inflammation or direct toxic damage. The aim of this study is to investigate the possible therapeutic effects of blockade of TRPC3/6 ion channels in the liver Carbon Tetra Chloride (CCl4) fibrosis model created in mice and the inflammatory pathways mediating this therapeutic effect at biochemical, histological and molecular levels. 50 male BALB/c mice, 10 animals in each group, Control, Sham (Pyr3+SAR7334;P+S), CCl4, CCl4+Pyr3+SAR7334 (CCl4+P+S) and CCl4+Colchicine. They were divided into (CCl4+Col) groups. Carbon tetra chloride (CCl4 30mg/kg), a hepatotoxin, was administered via oral gavage (OG) 3 times a week for a total of 6 weeks to induce liver fibrosis. Between weeks 3-6 of the experiment, colchicine (10mg/kg) was administered to the positive control group, TRPC3 inhibitor Pyr3 (10mg/kg/day, intraperitoneal) and TRPC6 inhibitor SAR7334 (2.5mg/kg/day, og) were administered simultaneously to the sham and treatment groups. Inflammation and fibrosis-related gene expressions in liver tissues after decapitation were analyzed by qRT-PCR, pathological deteriorations were analyzed by histological and serum samples by biochemical methods. Histologically, it was observed that this fibrosis appearance decreased in the treatment groups where CCl4 caused severe fibrosis. Biochemically, it was determined that AST, ALT, albumin and bulurubin levels, which increased as a result of exposure to CCl4, were normalized in the treatment groups. Our qRT-PCR analysis data showed that TRPC3, TRPC6, PPAR-β/NFATC1/NFATC3 expressions increased significantly, PPAR-α and PPAR-ɣ levels decreased in mice exposed to CCl4, and both colchicine and TRPC3/6 inhibition normalized these pathways. . It was determined that IL4 and IFN-ɣ increased with CCl4 exposure, largely normalizing the changes in cytokine levels. The study showed that TRPC3/6 inhibition has a significant therapeutic effect in alleviating hepatic toxicity in CCl4-induced liver damage and can improve hepatic dysfunction and prevent histopathological changes. Additionally, its mechanism is to reduce oxidative stress and inflammation.