Article

Ganoderic acid hinders renal fibrosis via suppressing the TGF- β/Smad and MAPK signaling pathways

Authors: Xiao-qiang Geng1, Ang Ma1, Jin-zhao He1, Liang Wang1, Ying-li Jia1, Guang-ying Shao1, Min Li1, Hong Zhou1, Shu-qian Lin2,3, Jian-hua Ran4, Bao-xue Yang1,5
1 State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
2 Fuzhou Institute of Green Valley Bio-Pharm Technology, Fuzhou 350002, China
3 JUNCAO Technology Research Institute, Fujian Agriculture and Forestry University, Fuzhou 350002, China
4 Department of Anatomy, and Laboratory of Neuroscience and Tissue Engineering, Basic Medical College, Chongqing Medical University, Chongqing 400016, China
5 Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China
Correspondence to: Bao-xue Yang: baoxue@bjmu.edu.cn,
DOI: 10.1038/s41401-019-0324-7
Received: 7 July 2019
Accepted: 20 September 2019
Advance online: 5 December 2019

Abstract

Renal fibrosis is considered as the pathway of almost all kinds of chronic kidney diseases (CKD) to the end stage of renal diseases (ESRD). Ganoderic acid (GA) is a group of lanostane triterpenes isolated from Ganoderma lucidum, which has shown a variety of pharmacological activities. In this study we investigated whether GA exerted antirenal fibrosis effect in a unilateral ureteral obstruction (UUO) mouse model. After UUO surgery, the mice were treated with GA (3.125, 12.5, and 50 mg· kg−1 ·d1, ip) for 7 or 14 days. Then the mice were sacrificed for collecting blood and kidneys. We showed that GA treatment dose-dependently attenuated UUO-induced tubular injury and renal fibrosis; GA (50 mg· kg−1 ·d1) significantly ameliorated renal disfunction during fibrosis progression. We further revealed that GA treatment inhibited the extracellular matrix (ECM) deposition in the kidney by suppressing the expression of fibronectin, mainly through hindering the over activation of TGF-β/Smad signaling. On the other hand, GA treatment significantly decreased the expression of mesenchymal cell markers alpha-smooth muscle actin (α-SMA) and vimentin, and upregulated E-cadherin expression in the kidney, suggesting the suppression of tubular epithelial-mesenchymal transition (EMT) partially via inhibiting both TGF-β/Smad and MAPK (ERK, JNK, p38) signaling pathways. The inhibitory effects of GA on TGF-β/Smad and MAPK signaling pathways were confirmed in TGF-β1-stimulated HK-2 cell model. GA-A, a GA monomer, was identified as a potent inhibitor on renal fibrosis in vitro. These data demonstrate that GA or GA-A might be developed as a potential therapeutic agent in the treatment of renal fibrosis.
Keywords: chronic kidney disease; renal fibrosis; ganoderic acid; epithelial-mesenchymal transition; TGF-β; UUO mice; HK-2 cells (human proximal tubular epithelial cells)

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