Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 6; pp. 2462 - 2467
• Main Authors: Takiar, Vinita, Nishio, Saori, Seo-Mayer, Patricia, King, J. Darwin Jr, Li, Hui, Zhang, Li, Karihaloo, Anil, Hallows, Kenneth R, Somlo, Stefan, Caplan, Michael J
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08-02-2011; National Acad Sciences
• Subjects: AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Autosomal dominant polycystic kidney; Biological Sciences; Cell growth; Cell Line; Cell lines; Cell Proliferation; Cells; Cystic fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Cysts; Cytogenetics; Disease models; Disease Models, Animal; Dogs; Epithelial cells; Epithelial Cells - enzymology; Epithelial Cells - pathology; Humans; Hypoglycemic Agents - pharmacology; Kidney diseases; Kidneys; Kinases; Metformin - pharmacology; Mice; Mice, Transgenic; Phosphorylation; Polycystic kidney diseases; Polycystic Kidney, Autosomal Dominant - enzymology; Polycystic Kidney, Autosomal Dominant - genetics; Polycystic Kidney, Autosomal Dominant - pathology; Rodents; Secretion; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1011498108

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.