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Targeting AMP-activated protein kinase (AMPK) for treatment of autosomal dominant polycystic kidney disease

机译：针对AMP活化的蛋白激酶（AMPK）治疗常染色体显性多囊肾疾病

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic kidney disease worldwide and an important cause of chronic kidney disease. Multiple experimental studies have highlighted the role of increased mammalian target of rapamycin complex 1 (mTORC1) and reduced AMP-activated protein kinase (AMPK) signaling in modulating cyst growth in ADPKD. Notably, mTORC1 and AMPK are two diametrically opposing sensors of energy metabolism which regulate cell growth and proliferation. Although pharmacological mTORC1 inhibition was highly effective in experimental studies of ADPKD, clinical trials of mTORC1 inhibitors showed a lack of efficacy with low-dose treatment and poor tolerability with high-dose treatment. Therapeutic AMPK activation has been shown to attenuate cystic kidney disease severity in Pkd1 mutant animal models by improving mitochondrial biogenesis and reducing tissue inflammation. This review summarizes the current knowledge on the function of AMPK as a regulator of cellular energy metabolism and how AMPK activation by pharmacological and non-pharmacological means can potentially be exploited to treat ADPKD in the clinical settings.
机译：常染色体占优势性多囊肾疾病（ADPKD）是全球最常见的单一的肾病和慢性肾病的重要原因。多个实验研究突出了哺乳动物复合物1（MTORC1）的增加哺乳动物靶标的作用以及减少的AMP活化蛋白激酶（AMPK）信号传导调节ADPKD的囊肿生长。值得注意的是，MTORC1和AMPK是两种直径相对的能量代谢传感器，其调节细胞生长和增殖。虽然药理MTORC1抑制在ADPKD的实验研究中具有高效的效果，但MTORC1抑制剂的临床试验表明缺乏低剂量治疗和具有高剂量处理的耐受性差的疗效差。已经显示治疗性AMPK激活通过改善线粒体生物发生和减少组织炎症，通过改善线粒体生物粒子和减少组织炎症来抑制PKD1突变动物模型中的囊性肾脏疾病严重程度。本综述总结了关于AMPK功能作为细胞能量代谢的调节剂的当前知识以及药理和非药物手段的AMPK激活如何潜在地在临床环境中治疗ADPKD。

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