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Human Molecular Genetics Advance Access published online on February 7, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn039
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1

Sekiya Shibazaki1, Zhiheng Yu1, Saori Nishio1, Xin Tian1, R. Brent Thomson1, Michihiro Mitobe1, Angeliki Louvi2, Heino Velazquez1, Shuta Ishibe1, Lloyd G. Cantley1, Peter Igarashi3 and Stefan Somlo1,4,*

1 Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 2 Neurosurgery, Yale University School of Medicine, New Haven, CT 3 Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 4 Genetics, Yale University School of Medicine, New Haven, CT

* Address correspondence to: Stefan Somlo, M.D. Section of Nephrology, Yale University School of Medicine, P.O. Box 208029, 333 Cedar Street, New Haven, CT 06520-8029, Phone: (203) 737-2974, Fax: (203) 785-4904, E-mail: stefan.somlo{at}yale.edu

Received November 17, 2007; Revised February 1, 2008; Accepted February 1, 2008

Polycystic kidney disease (ADPKD) results from failure of the kidney to properly maintain three dimensional structure after loss of either polycystin-1 or -2. Mice with kidney selective inactivation of Pkd1 during embryogenesis develop profound renal cystic disease and die from renal failure within three weeks of birth. In this model, cysts form exclusively from cells in which Cre recombinase is active, but the apparent pace of cyst expansion varies by segment and cell type. Intercalated cells do not participate in cyst expansion despite the presence of cilia up to at least postnatal day 21. Cystic segments show a persistent increase in proliferation as determined by BrdU incorporation; however, the absolute proliferative index is dependent on the underlying proliferative potential of kidney tubule cells. Components of the extracellular regulated kinase (MAPK/ERK) pathway from Ras through MEK1/2 and ERK1/2 to the effector P90RSK are activated in both perinatal Pkd1 and adult Pkd2 ortholgous gene disease models. The pattern of MAPK/ERK activation is focal and does not correlate with the pattern of active proliferation identified by BrdU uptake. The possibility of a causal relationship between ERK1/2 activation and cyst cell proliferation was assessed in vivo in the acute perinatal Pkd1 model of ADPKD using MEK1/2 inhibitor U0126. U0126 treatment had no effect on progression of cyst formation in this model at doses sufficient to reduce phospho-ERK1/2 in cystic kidneys. Cysts in ADPKD exhibit both increased proliferation and activation of MAPK/ERK, but cyst growth is not prevented by inhibition of ERK1/2 activation.


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