Knockout of Trpc6 attenuates T2DM-induced liver injury and inflammation by inhibiting CN-NFAT2-NLRP3 signalling in mice.

Diabetic liver disease is a common complication of diabetes mellitus that poses significant harm to patients. Transient receptor potential cation channel 6 (TRPC6) is a non-selective cation channel with calcium permeability, playing a key role in signalling pathways associated with liver disease progression. This study aimed to investigate the effects of Trpc6 knockout on liver injury and its regulation of the calcineurin (CN)-nuclear factor of activated T cells 2 (NFAT2) signalling pathway in mice with type 2 diabetes mellitus (T2DM). Serum aspartate aminotransferase and alanine aminotransferase levels were measured to assess liver function, while haematoxylin and eosin staining, periodic acid-Schiff staining, and Masson staining were used to evaluate pathological injury. Nile Red and Oil Red O staining were performed to assess hepatic lipid deposition. Western blotting, quantitative real-time polymerase chain reaction, and immunohistochemistry were used to analyse fibrosis- and inflammation-related markers in mouse liver tissues. The results showed that Trpc6 knockout had no significant effect on hepatic lipid deposition, CD36 expression, or phosphorylated phospholipase C levels in the liver tissues of mice with T2DM. However, Trpc6 knockout significantly inhibited NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome activation, thereby alleviating liver injury and fibrosis in mice with T2DM. Further findings indicated that Trpc6 knockout markedly reduced CN and NFAT2 expression in T2DM liver tissues and resisted intracellular calcium overload in liver cells in vitro. This study suggests that Trpc6 knockout attenuates T2DM-induced hepatic inflammation and fibrosis by inhibiting hepatocyte calcium overload and suppressing the CN-NFAT2-NLRP3 signalling pathway.