Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis.
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.
Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06520, USA.
Vinita
V
Takiar
Saori
S
Nishio
Patricia
P
Seo-Mayer
J Darwin
JD
King
Hui
H
Li
Li
L
Zhang
Anil
A
Karihaloo
Kenneth R
KR
Hallows
Stefan
S
Somlo
Michael J
MJ
Caplan
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D016891:Polycystic Kidney, Autosomal Dominant / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D007004:Hypoglycemic Agents; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D008687:Metformin; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
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