Poricoic acids PZC, PZD, and PZE attenuated epithelial-to-mesenchymal transition and extracellular matrix production in HK-2 cells and UUO mice by inhibiting Wnt/β-catenin and Smad3 pathways.
Do poricoic acids (PZC, PZD, PZE) prevent renal fibrosis in TGFβ1/AngII-treated HK-2 cells and UUO mice?
Novel poricoic acids isolated from Poria cocos demonstrate anti-fibrotic effects in preclinical models of chronic kidney disease by inhibiting the renin-angiotensin system and TGFβ/Smad pathways.
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.
Wang et al. (Sat,) conducted a other in Renal fibrosis. Poricoic acids (PZC, PZD, PZE) was evaluated on Epithelial-to-mesenchymal transition and extracellular matrix production. Poricoic acids PZC, PZD, and PZE attenuated epithelial-to-mesenchymal transition and extracellular matrix production in HK-2 cells and UUO mice by inhibiting Wnt/β-catenin and Smad3 pathways.
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