Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1
| Autor: | Angeliki Louvi, Zhiheng Yu, Sekiya Shibazaki, Stefan Somlo, Michihiro Mitobe, Saori Nishio, Shuta Ishibe, Lloyd G. Cantley, Xin Tian, Peter Igarashi, Heino Velazquez, R. Brent Thomson |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
medicine.medical_specialty TRPP Cation Channels MAP Kinase Kinase 2 MAP Kinase Kinase 1 Apoptosis Biology urologic and male genital diseases Kidney chemistry.chemical_compound Mice Internal medicine Nitriles Genetics medicine Polycystic kidney disease Butadienes Animals Cyst Molecular Biology Protein Kinase Inhibitors Genetics (clinical) Cell Proliferation Cystic kidney Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 PKD1 Kinase urogenital system Cysts General Medicine Articles medicine.disease Polycystic Kidney Autosomal Dominant Mice Mutant Strains Enzyme Activation Disease Models Animal medicine.anatomical_structure Endocrinology chemistry Cancer research Bromodeoxyuridine |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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