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Novel inhibitors of the cellular renin-angiotensin system components, poricoic acids, target Smad3 phosphorylation and Wnt/β-catenin pathway against renal fibrosis.
Br J Pharmacol. 2018 07; 175(13):2689-2708.BJ

Abstract

BACKGROUND AND PURPOSE

Tubulo-interstitial fibrosis is the final pathway in the progression of chronic kidney disease (CKD) to kidney failure. The renin-angiotensin system (RAS) plays a major role in CKD progression. Hence, we determined the efficacy of novel RAS inhibitors isolated from Poria cocos against renal fibrosis.

EXPERIMENTAL APPROACH

Effects of three novel tetracyclic triterpenoid compounds, poricoic acid ZC (PZC), poricoic acid ZD (PZD) and poricoic acid ZE (PZE), were investigated on TGFβ1- and angiotensin II (AngII)-treated HK-2 cells and unilateral ureteral obstruction (UUO) in mice. Immunofluorescence staining, quantitative real-time PCR, siRNA, co-immunoprecipitation and Western blot analyses were used to evaluate expression of key molecules in RAS, Wnt/β-catenin and TGFβ/Smad pathways.

KEY RESULTS

Addition of the above compounds to culture media and their administration to UUO mice: (i) significantly attenuated epithelial-to-mesenchymal transition and extracellular matrix production in TGFβ1- and AngII-treated HK-2 cells and UUO mice by inhibiting Wnt/β-catenin pathway activation and Smad3 phosphorylation; (ii) selectively inhibited Smad3 phosphorylation by blocking the interaction of TGFBR1 with Smad3; and (iii) specifically inhibited Smad3 activation. PZC and PZD showed a strong inhibitory effect on all RAS components, and PZE showed a strong inhibitory effect on renin. Furthermore, the secolanostane tetracyclic triterpenoids, PZC and PZD, showed a stronger inhibitory effect than the lanostane tetracyclic triterpenoid PZE. Therefore, compounds with secolanostance skeleton showed stronger bioactivity than those with lanostance skeleton.

CONCLUSION AND IMPLICATIONS

The secolanostane tetracyclic triterpenoids effectively blocked RAS by simultaneously targeting multiple RAS components and lanostane tetracyclic triterpenoids inhibited renin and protected against tubulo-interstitial fibrosis.

Authors+Show Affiliations

Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Science, Northwest University, Xi'an, Shaanxi, 710069, China.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Science, Northwest University, Xi'an, Shaanxi, 710069, China.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Science, Northwest University, Xi'an, Shaanxi, 710069, China.School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Science, Northwest University, Xi'an, Shaanxi, 710069, China.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Science, Northwest University, Xi'an, Shaanxi, 710069, China.Division of Nephrology and Hypertension, School of Medicine, University of California Irvine, Irvine, CA, 92897, USA.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Science, Northwest University, Xi'an, Shaanxi, 710069, China. Department of Internal Medicine, University of New Mexico, Comprehensive Cancer Center, Albuquerque, NM, 87131, USA.Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Life Science, Northwest University, Xi'an, Shaanxi, 710069, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29679507

Citation

Wang, Ming, et al. "Novel Inhibitors of the Cellular Renin-angiotensin System Components, Poricoic Acids, Target Smad3 Phosphorylation and Wnt/β-catenin Pathway Against Renal Fibrosis." British Journal of Pharmacology, vol. 175, no. 13, 2018, pp. 2689-2708.
Wang M, Chen DQ, Chen L, et al. Novel inhibitors of the cellular renin-angiotensin system components, poricoic acids, target Smad3 phosphorylation and Wnt/β-catenin pathway against renal fibrosis. Br J Pharmacol. 2018;175(13):2689-2708.
Wang, M., Chen, D. Q., Chen, L., Cao, G., Zhao, H., Liu, D., Vaziri, N. D., Guo, Y., & Zhao, Y. Y. (2018). Novel inhibitors of the cellular renin-angiotensin system components, poricoic acids, target Smad3 phosphorylation and Wnt/β-catenin pathway against renal fibrosis. British Journal of Pharmacology, 175(13), 2689-2708. https://doi.org/10.1111/bph.14333
Wang M, et al. Novel Inhibitors of the Cellular Renin-angiotensin System Components, Poricoic Acids, Target Smad3 Phosphorylation and Wnt/β-catenin Pathway Against Renal Fibrosis. Br J Pharmacol. 2018;175(13):2689-2708. PubMed PMID: 29679507.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel inhibitors of the cellular renin-angiotensin system components, poricoic acids, target Smad3 phosphorylation and Wnt/β-catenin pathway against renal fibrosis. AU - Wang,Ming, AU - Chen,Dan-Qian, AU - Chen,Lin, AU - Cao,Gang, AU - Zhao,Hui, AU - Liu,Dan, AU - Vaziri,Nosratola D, AU - Guo,Yan, AU - Zhao,Ying-Yong, Y1 - 2018/05/22/ PY - 2018/02/22/received PY - 2018/03/18/accepted PY - 2018/4/22/pubmed PY - 2019/9/26/medline PY - 2018/4/22/entrez SP - 2689 EP - 2708 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 175 IS - 13 N2 - BACKGROUND AND PURPOSE: Tubulo-interstitial fibrosis is the final pathway in the progression of chronic kidney disease (CKD) to kidney failure. The renin-angiotensin system (RAS) plays a major role in CKD progression. Hence, we determined the efficacy of novel RAS inhibitors isolated from Poria cocos against renal fibrosis. EXPERIMENTAL APPROACH: Effects of three novel tetracyclic triterpenoid compounds, poricoic acid ZC (PZC), poricoic acid ZD (PZD) and poricoic acid ZE (PZE), were investigated on TGFβ1- and angiotensin II (AngII)-treated HK-2 cells and unilateral ureteral obstruction (UUO) in mice. Immunofluorescence staining, quantitative real-time PCR, siRNA, co-immunoprecipitation and Western blot analyses were used to evaluate expression of key molecules in RAS, Wnt/β-catenin and TGFβ/Smad pathways. KEY RESULTS: Addition of the above compounds to culture media and their administration to UUO mice: (i) significantly attenuated epithelial-to-mesenchymal transition and extracellular matrix production in TGFβ1- and AngII-treated HK-2 cells and UUO mice by inhibiting Wnt/β-catenin pathway activation and Smad3 phosphorylation; (ii) selectively inhibited Smad3 phosphorylation by blocking the interaction of TGFBR1 with Smad3; and (iii) specifically inhibited Smad3 activation. PZC and PZD showed a strong inhibitory effect on all RAS components, and PZE showed a strong inhibitory effect on renin. Furthermore, the secolanostane tetracyclic triterpenoids, PZC and PZD, showed a stronger inhibitory effect than the lanostane tetracyclic triterpenoid PZE. Therefore, compounds with secolanostance skeleton showed stronger bioactivity than those with lanostance skeleton. CONCLUSION AND IMPLICATIONS: The secolanostane tetracyclic triterpenoids effectively blocked RAS by simultaneously targeting multiple RAS components and lanostane tetracyclic triterpenoids inhibited renin and protected against tubulo-interstitial fibrosis. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/29679507/Novel_inhibitors_of_the_cellular_renin_angiotensin_system_components_poricoic_acids_target_Smad3_phosphorylation_and_Wnt/β_catenin_pathway_against_renal_fibrosis_ L2 - https://doi.org/10.1111/bph.14333 DB - PRIME DP - Unbound Medicine ER -