Transient receptor potential channel 6 knockout ameliorates hepatic fibrosis by inhibiting the activation and proliferation of hepatic stellate cells.

Abstract

Background and aim: Hepatic fibrosis is a common outcome of chronic liver injury and can eventually lead to cirrhosis, which is a major public health concern. Hepatic stellate cells (HSCs) are the major producers of extracellular matrix (ECM) and regulate the synthesis and decomposition of ECM, but the specific mechanism of them remains unclear. Transient receptor potential channel 6 (TRPC6), a non-selective cation channel, plays an important role in organic fibrosis. However, the role of TRPC6 in liver fibrosis is rarely studied.

Methods: Here, we investigated the function of TRPC6 in the activation of the human hepatic stellate cell line LX-2 in vitro and bile duct ligation (BDL)-induced hepatic fibrosis in vivo by western blot, Ca²⁺ imaging, and immunohistochemistry.

Results: We first found that TRPC6 was upregulated in fibrotic liver tissues and TRPC6 knockout inhibited BDL-induced hepatic fibrosis. Transforming growth factor-β1 (TGF-β1) treatment increased TRPC6 expression and thapsigargin (Tg)-mediated SOCE in LX-2 cells, which was decreased by the TRPC6 specific inhibitor SAR7334. Blockage of TRPC6 by SAR7334 or TRPC6-shRNA transfection attenuated TGF-β1-induced LX-2 cell activation and proliferation via the PI3K/AKT/p70S6K signaling pathway.

Conclusions: These observations suggested that TRPC6 contribute to LX-2 cell activation and hepatic fibrosis, and downregulation of TRPC6 may become a therapeutic strategy for the treatment of hepatic fibrosis in the future.