Human Molecular Genetics Advance Access originally published online on February 7, 2008
Human Molecular Genetics 2008 17(11):1505-1516; doi:10.1093/hmg/ddn039
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1
1 Department of Internal Medicine 2 Department of Neurosurgery 3 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA 4 Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
* To whom correspondence should be addressed at: Section of Nephrology, Yale University School of Medicine, PO Box 208029, 333 Cedar Street, New Haven, CT 06520-8029, USA. Tel: +1 203 737 2974; Fax: +1 203 785 4904; Email: stefan.somlo{at}yale.edu
Received November 17, 2007; 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 3 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 bromodeoxyuridine (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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Happe, W. N. Leonhard, A. van der Wal, B. van de Water, I. S. Lantinga-van Leeuwen, M. H. Breuning, E. de Heer, and D. J.M. Peters Toxic tubular injury in kidneys from Pkd1-deletion mice accelerates cystogenesis accompanied by dysregulated planar cell polarity and canonical Wnt signaling pathways Hum. Mol. Genet., July 15, 2009; 18(14): 2532 - 2542. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Distefano, M. Boca, I. Rowe, C. Wodarczyk, L. Ma, K. B. Piontek, G. G. Germino, P. P. Pandolfi, and A. Boletta Polycystin-1 Regulates Extracellular Signal-Regulated Kinase-Dependent Phosphorylation of Tuberin To Control Cell Size through mTOR and Its Downstream Effectors S6K and 4EBP1 Mol. Cell. Biol., May 1, 2009; 29(9): 2359 - 2371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Hartman, D. Liu, J. T. Zilfou, V. Robb, T. Morrison, T. Watnick, and E. P. Henske The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway Hum. Mol. Genet., January 1, 2009; 18(1): 151 - 163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Battini, S. Macip, E. Fedorova, S. Dikman, S. Somlo, C. Montagna, and G. L. Gusella Loss of polycystin-1 causes centrosome amplification and genomic instability Hum. Mol. Genet., September 15, 2008; 17(18): 2819 - 2833. [Abstract] [Full Text] [PDF]
|
|