| Project/Area Number |
14570772
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Keio University |
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Principal Investigator |
AWAZU Midori Keio University, Department of Medicine, Assistant Professor, 医学部, 講師 (20129315)
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| Co-Investigator(Kenkyū-buntansha) |
HIDA Mairko Keio University, Department of Medicine, Instructor, 医学部, 助手 (20276306)
FUJITA Hisayo Keio University, Health Center, Instructor, 保健管理センター, 助手 (90296624)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | metanephric mesenchyma cell / bFGF / LIF / RPTPκ / ERK / p38 / polycystic kidney / organ culture / 腎発生 / 上皮化 / 細胞凝集 / MAPキナーゼ / 嚢胸腎 / DNAアレイ / 凝集 / 多発性嚢胞腎 / pcyマウス |
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| Research Abstract |
Incubation of rat metanephric mesenchymal cells with bFGF and LIF induced expression of an epithelial cell marker E-cadherin. The expression of E-cadherin was not affected by the blockade of ERK, but was suppressed by the blockade of p38. To identify genes that mediate the effect of p38, we analyzed patterns of gene expression in metanephroi cultured under a p38 inhibitor using CDNA microarray. Among downregulated genes by a p38 inhibitor, we found a signaling molecule receptor-like protein tyrosine phosphatase k (RPTPκ). RPTPκ belongs to the family of receptor-like tyrosine phosphatases and is implicated in cell adhesion and proliferation. The protein expression of RPTPκ during kidney development was identical to that of p38, and suppressed by a p38 inhibitor.
We next investigated the expression of MAP kinases in a murine model of polycystic kidney disease pcy mice. PCNA-positive cells were recognized in cyst epithelia from embryonic day 14 to 25 weeks of age. While ERK was expressed i
… More
n tubules of kidneys from control and pcy mice, stronger immunostaining was observed in cyst epithelia. Phosphorylated ERK was detected only in pcy mice localizing predominantly in cysts. p38 was no longer expressed after birth in controls, but was detected in cyst epithelia of pcy mice at all stages examined. JNK was expressed in all tubular segments of controls after neonatal day 7. In contrast, tubules and cysts of pcy kidneys expressed little JNK. Administration of a MEK inhibitor PD98059 to 6-week old pcy mice intraperitoneally for 4 weeks significantly decreased water intake, increased urine osmolality, and suppressed cyst formation. In conclusion, the expression of ERK, phosphorylated ERK, and p38 were upregulated, and that of JNK was downregulated in cyst epithelia of pcy mice. The inhibition of ERK suppressed cyst formation and alleviated the urinary concentrating defect. These resuks suggest that dysregulation of MAPKs, especially that of ERK, may play an important role in the pathophysiology of polycystic kidney disease and could be a novel therapeutic target. Less
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