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

Abstract

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.

Sirt3 Maintains Microvascular Endothelial Adherens Junction Integrity to Alleviate Sepsis‐Induced Lung Inflammation by Modulating the Interaction of VE‐Cadherin and β‐Catenin

“…TCF/LEF Reporter Assay. TCF/LEF reporter assay was carried out by the procedures described previously [13].…”

“…While the inhibition of β-catenin remarkably increases animal survival in the sepsis-induced ALI model [9], the activation of β-catenin contributes to inflammation through mediating the downstream target gene expression in ARDS/ALI [10,11]. Once triggered by Wnt ligands, the β-catenin protein is stabilized and accumulated in the cytoplasm and further translocates into the nucleus where βcatenin binds to T-cell factor/lymphoid enhancer factor (TCF/LEF) to initiate downstream target gene expression, including matrix metallopeptidase-7 (MMP-7) [12,13]. MMP-7 could increase permeability between endothelial cells [14].…”

Natural products: potential drugs for the treatment of renal fibrosis

“…Poricoic acid A is one of the main active ingredients in Poria cocos and has an excellent anti-renal fibrosis effect. In the UUO mice model, poricoic acid A reduced the activity of the Wnt/β-catenin signaling pathway by enhancing the expression of tryptophan hydroxylase-1 (TPH-1), and also inhibited renal cell injury and fibroblast activation, exerting an anti-renal fibrosis effect [ 56 ]. In addition, poricoic acid A can also inhibit renal fibrosis by activating the AMPK signaling pathway to inhibit TGF-β1/Smad3 pathway-mediated deposition of ECM and activation of myofibroblasts [ 57 ].…”

TGF-β/Smad Signaling Pathway in Tubulointerstitial Fibrosis

“…A number of poricoic acids, such as secolanostane tetracyclic triterpenoids and lanostane tetracyclic triterpenoids isolated and identified from Poria cocos protected against renal fibrosis by regulating Wnt1/β-catenin, IκB/NF-κB, and Keap1/Nrf2 pathways ( Wang et al, 2017 ; Chen et al, 2019c ; Wang et al, 2020 ). Poricoic acid A, a major component of Poria cocos , has been demonstrated to protect against renal fibrosis ( Chen et al, 2019d ; Chen et al, 2020a ; Chen et al, 2020b ). Previous study showed that poricoic acid A ameliorated AKI-to-CKD continuum by inhibiting Smad3 phosphorylation of renal tissues in renal ischemia-reperfusion injury rats ( Chen et al, 2019e ).…”