Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06520, USA.
Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2462-7. doi: 10.1073/pnas.1011498108. Epub 2011 Jan 24.
Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves both fluid secretion and abnormal proliferation of cyst-lining epithelial cells. The chloride channel of the cystic fibrosis transmembrane conductance regulator (CFTR) participates in secretion of cyst fluid, and the mammalian target of rapamycin (mTOR) pathway may drive proliferation of cyst epithelial cells. CFTR and mTOR are both negatively regulated by AMP-activated protein kinase (AMPK). Metformin, a drug in wide clinical use, is a pharmacological activator of AMPK. We find that metformin stimulates AMPK, resulting in inhibition of both CFTR and the mTOR pathways. Metformin induces significant arrest of cystic growth in both in vitro and ex vivo models of renal cystogenesis. In addition, metformin administration produces a significant decrease in the cystic index in two mouse models of ADPKD. Our results suggest a possible role for AMPK activation in slowing renal cystogenesis as well as the potential for therapeutic application of metformin in the context of ADPKD.
常染色体显性多囊肾病 (ADPKD) 中肾囊肿的发生和扩张既涉及囊液分泌，也涉及囊衬上皮细胞的异常增殖。囊性纤维化跨膜电导调节因子 (CFTR) 的氯离子通道参与囊液分泌，哺乳动物雷帕霉素靶蛋白 (mTOR) 途径可能驱动囊上皮细胞增殖。CFTR 和 mTOR 均受 AMP 激活的蛋白激酶 (AMPK) 负调控。二甲双胍是一种广泛应用于临床的药物，是 AMPK 的药理学激活剂。我们发现二甲双胍可刺激 AMPK，从而抑制 CFTR 和 mTOR 途径。二甲双胍可在体外和体内肾囊肿发生模型中显著抑制囊性生长。此外，二甲双胍给药可使两种 ADPKD 小鼠模型的囊肿指数显著降低。我们的研究结果表明，AMPK 激活可能在减缓肾囊肿发生中起作用，以及在 ADPKD 背景下应用二甲双胍进行治疗的潜力。
