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Regeneration of renal epithelial cells from metanephric mesenchymal cells

后肾间充质细胞再生肾上皮细胞

基本信息

批准号：
14570772
负责人：
AWAZU Midori
金额：
$ 2.18万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570772/
关键词：
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

项目摘要

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

bFGF和LIF孵育大鼠后肾间充质细胞诱导上皮细胞标记物E-cadherin的表达。阻断ERK不影响E-cadherin的表达，阻断p38则抑制E-cadherin的表达。为了鉴定介导p38作用的基因，我们使用cDNA微阵列分析了在p38抑制剂下培养的后肾中的基因表达模式。在p38抑制剂下调的基因中，我们发现了一个信号分子受体样蛋白酪氨酸磷酸酶K（RPTPκ）。RPTPκ属于受体样酪氨酸磷酸酶家族，与细胞粘附和增殖有关。RPTPκ在肾脏发育过程中的蛋白表达与p38的蛋白表达相同，并且被p38抑制剂抑制。PCNA阳性细胞在胚胎第14 ~ 25周的囊肿上皮中可见。而ERK在细胞内表达， ...更多信息在对照组和pcy小鼠的肾小管中，在囊肿上皮细胞中观察到较强的免疫染色。磷酸化ERK仅在pcy小鼠中检测到，主要定位于囊肿中。p38在对照组中出生后不再表达，但在所检查的所有阶段的pcy小鼠的囊肿上皮中检测到。JNK在新生儿7天后在对照组的所有肾小管节段中表达。相比之下，肾小管和囊肿的pcy肾表达很少JNK。给6周龄的pcy小鼠腹膜内施用MEK抑制剂PD 98059持续4周显著降低了水摄入量，增加了尿渗透压，并抑制了囊肿形成。结论：在pcy小鼠囊肿上皮中，ERK、磷酸化ERK和p38的表达上调，JNK的表达下调。抑制ERK的表达可抑制囊肿的形成，减轻尿浓缩缺陷。这些结果提示，MAPKs尤其是ERK的失调可能在多囊肾病的病理生理过程中起重要作用，并可能成为一个新的治疗靶点。少