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.

常染色体显性遗传多囊肾病 (ADPKD) 是最常见的威胁生命的单基因疾病之一，其特征是充满液体的肾囊肿进行性增大。我们之前的研究表明，灵芝三萜 (GT) 可延缓 PKD 肾囊肿的发展。在本研究中，我们确定了 GT 在抑制肾囊肿发展中的有效成分。使用体外MDCK cystogenesis 模型，我们将灵芝酸A (GA-A) 确定为12 种灵芝酸(GA) 单体中最有希望的候选者。我们进一步表明，GA-A（6.25-100 μM）在体外显着抑制MDCK囊肿模型和胚胎肾囊肿模型中的囊肿生长，并且抑制作用是可逆的。在肾脏特异性Pkd1表现出严重的囊性肾病的基因敲除(kPKD) 小鼠，给予GA-A (50 mg· kg ^-1  ·d ^-1 , sc) 显着减弱了肾囊肿的发展。在 kPKD 小鼠的 MDCK 细胞和肾脏中，我们发现 GA-A 剂量依赖性地下调 Ras/MAPK 信号通路。增殖细胞核抗原 (PCNA) 的表达也受到抑制，表明 GA-A 可能对细胞增殖产生影响。这些实验数据表明GA-A可能是GT的主要成分，作为治疗ADPKD的潜在治疗剂。