Ganoderic acid A is the effective ingredient of Ganoderma triterpenes in retarding renal cyst development in polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life-threatening monogenetic diseases characterized by progressive enlargement of fluid-filled renal cysts. Our previous study has shown that Ganoderma triterpenes (GT) retards PKD renal cyst development. In the present study we identified the effective ingredient of GT in suppression of kidney cyst development. Using an in vitro MDCK cystogenesis model, we identified ganoderic acid A (GA-A) as the most promising candidate among the 12 ganoderic acid (GA) monomers. We further showed that GA-A (6.25−100 μM) significantly inhibited cyst growth in MDCK cyst model and embryonic kidney cyst model in vitro, and the inhibitory effect was reversible. In kidney-specific Pkd1 knockout (kPKD) mice displaying severe cystic kidney disease, administration of GA-A (50 mg· kg−1 ·d−1, sc) significantly attenuated renal cyst development. In both MDCK cells and kidney of kPKD mice, we revealed that GA-A dose-dependently downregulated the Ras/MAPK signaling pathway. The expression of proliferating cell nuclear antigen (PCNA) was also suppressed, suggesting a possible effect of GA-A on cell proliferation. These experimental data suggest that GA-A may be the main ingredient of GT as a potential therapeutic reagent for treating ADPKD.

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Fig. 1: GA-A was identified as the active GT monomer using the MDCK cyst model.
Fig. 2: GA-A dose-dependently inhibited cyst formation and enlargement in the MDCK cyst model.
Fig. 3: GA-A inhibited renal cyst development in an embryonic kidney cyst model.
Fig. 4: GA-A repressed renal cyst development in an ADPKD mouse model.
Fig. 5: GA-A downregulated the Ras/MAPK signaling pathway in the FSK-treated MDCK cells and kidneys in the ADPKD mouse model.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China grants 81620108029, 81330074, 81261160507, 81170632, and 81873597 and the Beijing Natural Science Foundation grant 7172113. We thank Peter Igarashi and Stefan Somlo for the Ksp-Cre and Pkd1flox/flox mice.

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JM and BXY designed the study; JM, JZH, SZ, BYH, SYW, SZW, SQL, ML and HZ performed the experiments and analyzed the data; JM and BXY wrote the paper.

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Correspondence to Bao-xue Yang.

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Meng, J., Sai-zhen Wang, He, J. et al. Ganoderic acid A is the effective ingredient of Ganoderma triterpenes in retarding renal cyst development in polycystic kidney disease. Acta Pharmacol Sin 41, 782–790 (2020). https://doi.org/10.1038/s41401-019-0329-2

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Keywords

  • ADPKD
  • Ganoderma triterpenes
  • Ganoderic acids
  • Ganoderic acid A
  • MDCK
  • kPKD mice
  • Ras/MAPK signaling pathway
  • 8-Br-cAMP

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