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

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.

New insights into TGF-β/Smad signaling in tissue fibrosis

“…Poricoic acid ZC, poricoic acid ZD and poricoic acid ZE treatment significant attenuated EMT production by inhibiting specific Smad3 phosphorylation by blocking the interaction of TGFβRI with Smad3 signaling in both TGF-β1-and AngII-treated HK-2 cells and unilateral ureteralocclusion (UUO) mice [93]. Poricoic acid ZG and poricoic acid ZH is used for treating podocyte injury and renal fibrosis [94]. Poricoic acid ZG and poricoic acid ZH were also used for renal disease by inhibiting TGF-β/Smad pathway which selectively inhibiting the phosphorylation of Smad3 via blocking the interactions of SARA with TGFβRI and Smad3 [94].…”

“…Poricoic acid ZG and poricoic acid ZH is used for treating podocyte injury and renal fibrosis [94]. Poricoic acid ZG and poricoic acid ZH were also used for renal disease by inhibiting TGF-β/Smad pathway which selectively inhibiting the phosphorylation of Smad3 via blocking the interactions of SARA with TGFβRI and Smad3 [94].…”

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…[159][160][161] New triterpenoids, including poricoic acid ZC, poricoic acid ZD, and poricoic acid ZE, significantly downregulated the expression of Wnt1, active β-catenin, Snail, Twist, MMP-7, PAI-1, and FSP1 in HK-2 cells induced by TGF-β1 and angiotensin II and mice with unilateral ureteral occlusion 29 (Figure 2 and Table 1). Moreover, new triterpenoids, including poricoic acid ZG and poricoic acid ZH, improved renal fibrosis by targeting the phosphorylation of Smad3 signaling and the Wnt/β-catenin signaling pathway 162 (Figure 2 and Table 1).…”

Establishment and application of a method for screening the therapeutic drugs of ethanol‐induced liver injury based on cellular metabonomics

“…The cell viability assay was followed from a previous publication and is briefly summarized as follows (Wang et al, 2018;Wang et al, 2017). L-02 cells were seeded in 96-well plates at a density of 5 × 10 3 cells per well.…”