新型细胞肾素-血管紧张素系统成分抑制剂——云芝酸通过靶向 Smad3 磷酸化和 Wnt/β-连环蛋白通路抑制肾纤维化。
Novel inhibitors of the cellular renin-angiotensin system components, poricoic acids, target Smad3 phosphorylation and Wnt/β-catenin pathway against renal fibrosis.
机构信息
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.
出版信息
Br J Pharmacol. 2018 Jul;175(13):2689-2708. doi: 10.1111/bph.14333. Epub 2018 May 22.
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.
背景与目的
肾小管间质纤维化是慢性肾脏病（CKD）进展为肾衰竭的终末途径。肾素-血管紧张素系统（RAS）在 CKD 进展中起主要作用。因此，我们确定了从茯苓中分离出的新型 RAS 抑制剂对肾纤维化的疗效。
实验方法
研究了三种新型四环三萜化合物，即猪苓酸 ZC（PZC）、猪苓酸 ZD（PZD）和猪苓酸 ZE（PZE），对 TGFβ1 和血管紧张素 II（AngII）处理的 HK-2 细胞以及单侧输尿管梗阻（UUO）小鼠的影响。免疫荧光染色、实时定量 PCR、siRNA、共免疫沉淀和 Western blot 分析用于评估 RAS、Wnt/β-catenin 和 TGFβ/Smad 通路中关键分子的表达。
主要结果
将上述化合物添加到培养基中，并在 UUO 小鼠中给药：（i）通过抑制 Wnt/β-catenin 通路的激活和 Smad3 磷酸化，显著减弱了 TGFβ1 和 AngII 处理的 HK-2 细胞和 UUO 小鼠中的上皮间质转化和细胞外基质产生；（ii）通过阻断 TGFBR1 与 Smad3 的相互作用，选择性抑制 Smad3 磷酸化；（iii）特异性抑制 Smad3 激活。PZC 和 PZD 对所有 RAS 成分均表现出强烈的抑制作用，PZE 对肾素有强烈的抑制作用。此外，四环三萜化合物 PZC 和 PZD 对 RAS 的抑制作用强于五环四环三萜化合物 PZE。因此，四环四环三萜化合物的骨架具有比五环四环三萜化合物更强的生物活性。
结论与意义
四环三萜化合物通过同时靶向多个 RAS 成分有效地阻断了 RAS，而五环四环三萜化合物抑制了肾素并防止了肾小管间质纤维化。
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