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

Sekiya Shibazaki, Zhiheng Yu, Saori Nishio, Xin Tian, R. Brent Thomson, Michihiro Mitobe, Angeliki Louvi, Heino Velazquez, Shuta Ishibe, Lloyd G. Cantley, Peter Igarashi, Stefan Somlo

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Abstract

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 P90 RSK > 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.

Original languageEnglish (US)
Pages (from-to)1505-1516
Number of pages12
JournalHuman Molecular Genetics
Volume17
Issue number11
DOIs
StatePublished - Jun 2008

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Cysts
Phosphotransferases
Kidney
Autosomal Dominant Polycystic Kidney
Cystic Kidney Diseases
Bromodeoxyuridine
Renal Insufficiency
Kidney Tubules
Polycystic Kidney Diseases
MAP Kinase Signaling System
Cilia
Mitogen-Activated Protein Kinase Kinases
Embryonic Development
Cell Proliferation
Parturition
Growth
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Shibazaki, S., Yu, Z., Nishio, S., Tian, X., Thomson, R. B., Mitobe, M., ... Somlo, S. (2008). Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Human Molecular Genetics, 17(11), 1505-1516. https://doi.org/10.1093/hmg/ddn039

Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. / Shibazaki, Sekiya; Yu, Zhiheng; Nishio, Saori; Tian, Xin; Thomson, R. Brent; Mitobe, Michihiro; Louvi, Angeliki; Velazquez, Heino; Ishibe, Shuta; Cantley, Lloyd G.; Igarashi, Peter; Somlo, Stefan.

In: Human Molecular Genetics, Vol. 17, No. 11, 06.2008, p. 1505-1516.

Research output: Contribution to journalArticle

Shibazaki, S, Yu, Z, Nishio, S, Tian, X, Thomson, RB, Mitobe, M, Louvi, A, Velazquez, H, Ishibe, S, Cantley, LG, Igarashi, P & Somlo, S 2008, 'Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1', Human Molecular Genetics, vol. 17, no. 11, pp. 1505-1516. https://doi.org/10.1093/hmg/ddn039
Shibazaki, Sekiya ; Yu, Zhiheng ; Nishio, Saori ; Tian, Xin ; Thomson, R. Brent ; Mitobe, Michihiro ; Louvi, Angeliki ; Velazquez, Heino ; Ishibe, Shuta ; Cantley, Lloyd G. ; Igarashi, Peter ; Somlo, Stefan. / Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 11. pp. 1505-1516.
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