Poricoic acid A as a modulator of TPH-1 expression inhibits renal fibrosis via modulating protein stability of β-catenin and β-catenin-mediated transcription.

BACKGROUND:Renal fibrosis is the common feature of chronic kidney disease (CKD). However, few drugs specifically target fibrogenesis due to the lack of an effective therapeutic target. Hence, it is urgent to find a therapeutic strategy that inhibits renal fibrosis. Here, we identified that poricoic acid A (PAA) as the modulator of tryptophan hydroxylase-1 (TPH-1), the key enzyme in tryptophan metabolism, exerted potent anti-fibrotic effects in the kidney. METHODS:Lentiviral vector, luciferase reporter activity assay and co-immunoprecipitation were used. The animal model of unilateral ureteral obstruction and adenine-induced chronic renal failure as well as transforming growth factor (TGF)-β1-treated epithelial cells NRK-52E and fibroblasts NRK-49F were used. RESULTS:TPH-1 was gradually decreased during CKD progression, while PAA treatment significantly increased TPH-1 expression to suppress renal fibrosis. Pharmacological overexpression of TPH-1 by PAA treatment exhibited anti-fibrosis and was linked to Wnt/β-catenin signaling activity. TPH-1 exhibited anti-fibrotic effects by suppressing epithelial cell injury and fibroblast activation, and PAA promoted TPH-1 expression and then suppressed the Wnt/β-catenin signaling pathway via regulating the protein stability of β-catenin and β-catenin-mediated transcription. TPH-1 overexpression enhanced the anti-fibrotic effects of PAA, while TPH-1 deficiency weakened the anti-fibrotic effects of PAA, indicating that TPH-1 was required for the anti-fibrotic effects of PAA. CONCLUSION:PAA as a modulator of TPH-1 expression attenuated renal fibrosis through regulating the Wnt/β-catenin signaling pathway by acting on the protein stability of β-catenin and β-catenin-mediated transcription. TPH-1 was required for PAA to exert anti-fibrosis.