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Novel RAS Inhibitors Poricoic Acid ZG and Poricoic Acid ZH Attenuate Renal Fibrosis via a Wnt/β-Catenin Pathway and Targeted Phosphorylation of smad3 Signaling.
J Agric Food Chem. 2018 Feb 28; 66(8):1828-1842.JA

Abstract

Renal fibrosis is a common end point of the progression of chronic kidney disease (CKD). Suppressing the development and progression of renal fibrosis is essential in the treatment of kidney disease. Our previous study demonstrated that the ethyl acetate extract of the surface layer of Poria cocos exhibited beneficial antitubulointerstitial fibrosis. In this study, we isolated new diterpene (PZF) and triterpenes (PZG and PZH) and examined their antifibrotic effect. TGF-β1 upregulated the collagen I protein expression in HK-2 cells, and PZG and PZH treatment significantly inhibited the upregulated collagen I expression (TGF group 0.59 ± 0.08 vs TGF+PZG group 0.36 ± 0.08, P < 0.01; TGF+PZH group 0.39 ± 0.12, P < 0.01). Triterpenes, PZG and PZH, exhibited a stronger inhibitory effect on renal fibrosis and podocyte injury than PZF. PZG and PZH further showed a stronger inhibitory effect on the activation of the renin-angiotensin system (RAS) than PZF. Additionally, PZG and PZH markedly inhibited the activation of Wnt/β-catenin signaling, which played an important role in fibrogenesis. Interestingly, PZG and PZH suppressed the TGF-β/Smad pathway by selectively inhibiting the phosphorylation of Smad3 through blocking the interactions of SARA with TGFβI and Smad3. The analysis of the structure-activity relationship demonstrated that their antifibrotic effects were closely associated with the first six-membered ring structure and the number of carboxyl groups in this type of compounds. Additionally, fifteen known triterpenes were identified. These novel tetracyclic triterpenoid compounds provided the potential lead compounds for the research and development of antifibrosis drug, and they possessed the potential to be utilized as RAS inhibitors.

Authors+Show Affiliations

Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Science, 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 Science, 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 Science, 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 Science, 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 Science, 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 Science, Northwest University , No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China.Division of Nephrology and Hypertension, School of Medicine, University of California-Irvine , Irvine, California 92897, United States.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Science, Northwest University , No. 229 Taibai North Road, Xi'an, Shaanxi 710069, China. Department of Internal Medicine, University of New Mexico , Comprehensive Cancer Center, Albuquerque, New Mexico 87131, United States.No affiliation info availableSchool of Pharmacy, Zhejiang Chinese Medical University , No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29383936

Citation

Wang, Ming, et al. "Novel RAS Inhibitors Poricoic Acid ZG and Poricoic Acid ZH Attenuate Renal Fibrosis Via a Wnt/β-Catenin Pathway and Targeted Phosphorylation of Smad3 Signaling." Journal of Agricultural and Food Chemistry, vol. 66, no. 8, 2018, pp. 1828-1842.
Wang M, Chen DQ, Chen L, et al. Novel RAS Inhibitors Poricoic Acid ZG and Poricoic Acid ZH Attenuate Renal Fibrosis via a Wnt/β-Catenin Pathway and Targeted Phosphorylation of smad3 Signaling. J Agric Food Chem. 2018;66(8):1828-1842.
Wang, M., Chen, D. Q., Chen, L., Liu, D., Zhao, H., Zhang, Z. H., Vaziri, N. D., Guo, Y., Zhao, Y. Y., & Cao, G. (2018). Novel RAS Inhibitors Poricoic Acid ZG and Poricoic Acid ZH Attenuate Renal Fibrosis via a Wnt/β-Catenin Pathway and Targeted Phosphorylation of smad3 Signaling. Journal of Agricultural and Food Chemistry, 66(8), 1828-1842. https://doi.org/10.1021/acs.jafc.8b00099
Wang M, et al. Novel RAS Inhibitors Poricoic Acid ZG and Poricoic Acid ZH Attenuate Renal Fibrosis Via a Wnt/β-Catenin Pathway and Targeted Phosphorylation of Smad3 Signaling. J Agric Food Chem. 2018 Feb 28;66(8):1828-1842. PubMed PMID: 29383936.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel RAS Inhibitors Poricoic Acid ZG and Poricoic Acid ZH Attenuate Renal Fibrosis via a Wnt/β-Catenin Pathway and Targeted Phosphorylation of smad3 Signaling. AU - Wang,Ming, AU - Chen,Dan-Qian, AU - Chen,Lin, AU - Liu,Dan, AU - Zhao,Hui, AU - Zhang,Zhi-Hao, AU - Vaziri,Nosratola D, AU - Guo,Yan, AU - Zhao,Ying-Yong, AU - Cao,Gang, Y1 - 2018/02/14/ PY - 2018/2/1/pubmed PY - 2018/3/13/medline PY - 2018/2/1/entrez KW - Poria cocos KW - TGF-β/Smad pathway KW - Wnt/β-catenin pathway KW - poricoic acid KW - renin−angiotensin system SP - 1828 EP - 1842 JF - Journal of agricultural and food chemistry JO - J. Agric. Food Chem. VL - 66 IS - 8 N2 - Renal fibrosis is a common end point of the progression of chronic kidney disease (CKD). Suppressing the development and progression of renal fibrosis is essential in the treatment of kidney disease. Our previous study demonstrated that the ethyl acetate extract of the surface layer of Poria cocos exhibited beneficial antitubulointerstitial fibrosis. In this study, we isolated new diterpene (PZF) and triterpenes (PZG and PZH) and examined their antifibrotic effect. TGF-β1 upregulated the collagen I protein expression in HK-2 cells, and PZG and PZH treatment significantly inhibited the upregulated collagen I expression (TGF group 0.59 ± 0.08 vs TGF+PZG group 0.36 ± 0.08, P < 0.01; TGF+PZH group 0.39 ± 0.12, P < 0.01). Triterpenes, PZG and PZH, exhibited a stronger inhibitory effect on renal fibrosis and podocyte injury than PZF. PZG and PZH further showed a stronger inhibitory effect on the activation of the renin-angiotensin system (RAS) than PZF. Additionally, PZG and PZH markedly inhibited the activation of Wnt/β-catenin signaling, which played an important role in fibrogenesis. Interestingly, PZG and PZH suppressed the TGF-β/Smad pathway by selectively inhibiting the phosphorylation of Smad3 through blocking the interactions of SARA with TGFβI and Smad3. The analysis of the structure-activity relationship demonstrated that their antifibrotic effects were closely associated with the first six-membered ring structure and the number of carboxyl groups in this type of compounds. Additionally, fifteen known triterpenes were identified. These novel tetracyclic triterpenoid compounds provided the potential lead compounds for the research and development of antifibrosis drug, and they possessed the potential to be utilized as RAS inhibitors. SN - 1520-5118 UR - https://www.unboundmedicine.com/medline/citation/29383936/Novel_RAS_Inhibitors_Poricoic_Acid_ZG_and_Poricoic_Acid_ZH_Attenuate_Renal_Fibrosis_via_a_Wnt/β_Catenin_Pathway_and_Targeted_Phosphorylation_of_smad3_Signaling_ L2 - https://dx.doi.org/10.1021/acs.jafc.8b00099 DB - PRIME DP - Unbound Medicine ER -