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

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.

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Fig. 1: GA hindered tubular injury and renal fibrosis induced by UUO.
Fig. 2: GA hindered renal tubular EMT progression in the UUO mouse model.
Fig. 3: GA inhibited the TGF-β/Smad and MAPK signaling pathways in vivo.
Fig. 4: GA inhibited the TGF-β/Smad and MAPK signaling pathways in HK-2 cells.
Fig. 5: Inhibitory effect of the GA monomers GA-A, GA-B, and GA-C on fibrosis in vitro.
Fig. 6: Schematic diagram of the proposed underlying mechanisms involved in the antirenal fibrotic activity of GA.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grants 81620108029, 81330074, 81261160507, 81974083, 81170632 and 81770738) and the Beijing Natural Science Foundation (grant 7172113).

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Contributions

XQG and BXY designed the research. XQG, AM, JZH, YLJ, LW, GYS, ML, and JHR performed the research. XQG, JHR, and SQL analyzed the data. XQG and BXY wrote the manuscript. HZ and BXY revised the manuscript.

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Correspondence to Bao-xue Yang.

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The authors declare no competing interests.

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Geng, X., Ma, A., He, J. et al. Ganoderic acid hinders renal fibrosis via suppressing the TGF-β/Smad and MAPK signaling pathways. Acta Pharmacol Sin 41, 670–677 (2020). https://doi.org/10.1038/s41401-019-0324-7

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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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