| Autor: |
Takiar V; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06520, USA., Nishio S, Seo-Mayer P, King JD Jr, Li H, Zhang L, Karihaloo A, Hallows KR, Somlo S, Caplan MJ |
| Jazyk: |
angličtina |
| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2011 Feb 08; Vol. 108 (6), pp. 2462-7. Date of Electronic Publication: 2011 Jan 24. |
| DOI: |
10.1073/pnas.1011498108 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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