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Poricoic acid ZA, a novel RAS inhibitor, attenuates tubulo-interstitial fibrosis and podocyte injury by inhibiting TGF-β/Smad signaling pathway.
Phytomedicine. 2017 Dec 01; 36:243-253.P

Abstract

BACKGROUND

The pathogenesis of tubulo-interstitial fibrosis and glomerulosclerosisis was characterized by cellular hypertrophy, extracellular matrix accumulation and podocyte detachment. Poricoic acid ZA (PZA) is a tetracyclic triterpenoid compound extracted from the surface layer of Poria cocos (LPC), which have been used extensively for diuretic and renoprotective effects.

METHODS

The anti-fibrotic effect of PZA is investigated in HK-2 cells and podocytes induced by TGF-β1 and angiotensin II (ANGII). qRT-PCR, siRNA, immunofluorescence staining, co-immunoprecipitation and Western blot analyses are used to evaluate the expression of RAS signaling, TGF-β/Smad pathway, epithelial-to-mesenchymal transition (EMT) and podocyte markers.

RESULTS

PZA restores the mRNA and protein expression of EMT in HK-2 cells. Specific TGF-β1-siRNA efficiently blocks ANGII-induced protein expression of TGF-β1 and further inhibits activated Smad signaling. PZA significantly attenuates up-regulation of angiotensinogen, renin, ACE and AT1. Further, PZA reverses up-regulation of TGFβRII and suppresses Smad proteins. Simultaneously, PZA inhibits the protein interaction of TGF-β receptor and Smads and PZA also inhibits activated RAS and TGF-β/Smad signaling cascade and up-regulates protein expression of podocyte markers and mitigates podocyte injury.

CONCLUSIONS

This study demonstrated the beneficial role of PZA in renal fibrosis and podocyte injury. Our study highlighted that PZA inhibits RAS and further suppresses TGF-β/Smad pathway through inhibiting Smad2/3 phosphorylation via blocking Smad2/3-TGFβRI protein interaction. PZA is implicated in activation of RAS/TGF-β/Smad axis in HK-2 cells and podocytes. PZA could be considered as a novel RAS inhibitor for treating CKD.

Authors+Show Affiliations

Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.Xi'an Modern Chemistry Institute, Xi'an, Shaanxi 710065, China.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Sciences, Northwest University, No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China. Electronic address: zyy@nwu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29157821

Citation

Wang, Ming, et al. "Poricoic Acid ZA, a Novel RAS Inhibitor, Attenuates Tubulo-interstitial Fibrosis and Podocyte Injury By Inhibiting TGF-β/Smad Signaling Pathway." Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, vol. 36, 2017, pp. 243-253.
Wang M, Chen DQ, Wang MC, et al. Poricoic acid ZA, a novel RAS inhibitor, attenuates tubulo-interstitial fibrosis and podocyte injury by inhibiting TGF-β/Smad signaling pathway. Phytomedicine. 2017;36:243-253.
Wang, M., Chen, D. Q., Wang, M. C., Chen, H., Chen, L., Liu, D., Zhao, H., & Zhao, Y. Y. (2017). Poricoic acid ZA, a novel RAS inhibitor, attenuates tubulo-interstitial fibrosis and podocyte injury by inhibiting TGF-β/Smad signaling pathway. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, 36, 243-253. https://doi.org/10.1016/j.phymed.2017.10.008
Wang M, et al. Poricoic Acid ZA, a Novel RAS Inhibitor, Attenuates Tubulo-interstitial Fibrosis and Podocyte Injury By Inhibiting TGF-β/Smad Signaling Pathway. Phytomedicine. 2017 Dec 1;36:243-253. PubMed PMID: 29157821.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Poricoic acid ZA, a novel RAS inhibitor, attenuates tubulo-interstitial fibrosis and podocyte injury by inhibiting TGF-β/Smad signaling pathway. AU - Wang,Ming, AU - Chen,Dan-Qian, AU - Wang,Min-Chang, AU - Chen,Hua, AU - Chen,Lin, AU - Liu,Dan, AU - Zhao,Hui, AU - Zhao,Ying-Yong, Y1 - 2017/10/12/ PY - 2017/06/28/received PY - 2017/09/03/revised PY - 2017/10/10/accepted PY - 2017/11/22/entrez PY - 2017/11/22/pubmed PY - 2018/5/16/medline KW - Epithelial-to-mesenchymal transition KW - Podocyte KW - Poria cocos KW - Poricoic acid ZA KW - Renal fibrosis KW - Renin–angiotensin system SP - 243 EP - 253 JF - Phytomedicine : international journal of phytotherapy and phytopharmacology JO - Phytomedicine VL - 36 N2 - BACKGROUND: The pathogenesis of tubulo-interstitial fibrosis and glomerulosclerosisis was characterized by cellular hypertrophy, extracellular matrix accumulation and podocyte detachment. Poricoic acid ZA (PZA) is a tetracyclic triterpenoid compound extracted from the surface layer of Poria cocos (LPC), which have been used extensively for diuretic and renoprotective effects. METHODS: The anti-fibrotic effect of PZA is investigated in HK-2 cells and podocytes induced by TGF-β1 and angiotensin II (ANGII). qRT-PCR, siRNA, immunofluorescence staining, co-immunoprecipitation and Western blot analyses are used to evaluate the expression of RAS signaling, TGF-β/Smad pathway, epithelial-to-mesenchymal transition (EMT) and podocyte markers. RESULTS: PZA restores the mRNA and protein expression of EMT in HK-2 cells. Specific TGF-β1-siRNA efficiently blocks ANGII-induced protein expression of TGF-β1 and further inhibits activated Smad signaling. PZA significantly attenuates up-regulation of angiotensinogen, renin, ACE and AT1. Further, PZA reverses up-regulation of TGFβRII and suppresses Smad proteins. Simultaneously, PZA inhibits the protein interaction of TGF-β receptor and Smads and PZA also inhibits activated RAS and TGF-β/Smad signaling cascade and up-regulates protein expression of podocyte markers and mitigates podocyte injury. CONCLUSIONS: This study demonstrated the beneficial role of PZA in renal fibrosis and podocyte injury. Our study highlighted that PZA inhibits RAS and further suppresses TGF-β/Smad pathway through inhibiting Smad2/3 phosphorylation via blocking Smad2/3-TGFβRI protein interaction. PZA is implicated in activation of RAS/TGF-β/Smad axis in HK-2 cells and podocytes. PZA could be considered as a novel RAS inhibitor for treating CKD. SN - 1618-095X UR - https://www.unboundmedicine.com/medline/citation/29157821/Poricoic_acid_ZA_a_novel_RAS_inhibitor_attenuates_tubulo_interstitial_fibrosis_and_podocyte_injury_by_inhibiting_TGF_β/Smad_signaling_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0944-7113(17)30149-6 DB - PRIME DP - Unbound Medicine ER -