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

被引:25
作者
Chen, Dan-Qian [1 ,2 ]
Wu, Xia-Qing [1 ]
Chen, Lin [1 ]
Hu, He-He [1 ]
Wang, Yan-Ni [1 ]
Zhao, Ying-Yong [1 ]
机构
[1] Northwest Univ, Fac Life Sci & Med, 229 Taibai North Rd, Xian 710069, Shaanxi, Peoples R China
[2] China Japan Friendship Hosp, Inst Clin Med Sci, Dept Pharmacol, Beijing Key Lab Immune Mediated Inflammatory Dis, Beijing, Peoples R China
基金
中国国家自然科学基金;
关键词
chronic kidney disease; fibroblast; poricoic acid A; TPH-1; renal fibrosis; Wnt/beta-catenin; PERFORMANCE LIQUID-CHROMATOGRAPHY; TO-MESENCHYMAL TRANSITION; TUBULOINTERSTITIAL FIBROSIS; DIURETIC ACTIVITY; PODOCYTE INJURY; RAS INHIBITOR; TGF-BETA/SMAD; PORIA-COCOS; METABOLOMICS; MECHANISMS;
D O I
10.1177/2040622320962648
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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)-beta 1-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/beta-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/beta-catenin signaling pathwayviaregulating the protein stability of beta-catenin and beta-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/beta-catenin signaling pathway by acting on the protein stability of beta-catenin and beta-catenin-mediated transcription. TPH-1 was required for PAA to exert anti-fibrosis.
引用
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页数:17
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