Rele of MAP kinases in normal and abnormal renal development

MAP 激酶与正常和异常肾脏发育的关系

• 批准号: 10670757
• 负责人: AWAZU Midori
• 金额: $ 1.86万
• 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: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670757/
• 关键词: MAP kinase; ERK; p38 MAP kinase; JNK; development; kidney; signaling; anomaly; P38MAPキナーゼ; 後腎間葉細胞; p38MAPキナーゼ; P38; MKP-1; 分化; p38

We investigated the role of mitogen-activated protein kinase (MAPK) family, a critical enzyme in cellular signaling, in normal and abnormal renal development. Extracellular signal-regulated kinase (ERK), p38 MAPK (p38), and MAPK phosphatase-1 (MKP-1) are strongly expressed in the developing kidney, and JNK is detected predominantly in the adult kidney. Both the temporal and spatial expression of ERK coincides with the maturation of the kidney.We next investigated the role of ERK and p38 in organ culture system using ERK or p38 inhibitors. Both ERK and p38 are demonstrated to be necessary for renal development. ERK appears to play a role in nephrogenesis and p38 for kidney growth and nephrogenesis.Next the role of MAPKs in abnormal kidney development was examined. p38 is ectopically expressed, and JNK is downregulated in dysplastic epithelia of human multicystic dysplastic kidney. Furthermore, dysplastic epithelia are exclusively positive for ERK and P-ERK. Activated p38 and ERK may med … More iate hyperproliferation of dysplastic tubules resulting in cyst formation/whereas downregulated JNK expression may be the cause or the result of an undifferentiated state of dysplastic epithelia. The same pattern of MAPK dysregulation was observed in the mouse model of polycystic kidney disease.Fibroblast growth factor 2 (FGF2) prevents apoptosis and stimulates proliferation of metanephric mesenchymal cells (MMCs). The cellular signaling of FGF2 in MMCs has not yet been clarified. We therefore investigated whether p38 and ERK were involved in FGF2-induced mitogenesis and migration of MMCs. Our results showed that both p38 and ERK are activated by FGF2 and mediate FGF2-induced mitogenesis and migration of MMCs.Since dysplastic kidneys are commonly associated with fetal urinary tract obstruction, we investigated the expression-of MAPKs in ovine model of fetal urinary tract obstruction. Similarly to human multicystic dysplastic kidney and mouse polycystic kidney. p38, ERK are upregulated and JNK was downregulated in cyst epithelia and dysplastic tubules.In conclusion, we have demonstrated that MAPKs play an important role in normal and abnormal kidney development. Less

我们研究了丝裂原活化蛋白激酶（MAPK）家族在正常和异常肾脏发育中的作用。细胞外信号调节激酶（ERK）、p38 MAPK（p38）和MAPK磷酸酶-1（MKP-1）在发育中的肾脏中强烈表达，JNK主要在成年肾脏中检测到。ERK的时空表达与肾脏的成熟过程相一致，本研究利用ERK或p38抑制剂研究ERK和p38在器官培养体系中的作用。ERK和p38都被证明是肾脏发育所必需的。ERK似乎在肾发生中起作用，p38在肾生长和肾发生中起作用。p38在人多囊性发育不良肾的发育不良上皮中异位表达，JNK下调。此外，发育不良的上皮细胞仅对ERK和P-ERK呈阳性。活化的p38和ERK可能介导 ...更多信息 发育不良小管的晚期过度增殖导致囊肿形成，而JNK表达下调可能是发育不良上皮细胞未分化状态的原因或结果。成纤维细胞生长因子2（FGF 2）可抑制后肾间充质细胞（MMCs）的凋亡并促进其增殖。FGF 2在MMC中的细胞信号传导尚未阐明。因此，我们研究了p38和ERK是否参与FGF 2诱导的有丝分裂和MMCs迁移。我们的研究结果表明，p38和ERK都被FGF 2激活，并介导FGF 2诱导的有丝分裂和MMCs的迁移。由于发育不良的肾脏通常与胎儿尿路梗阻有关，我们研究了MAPK在胎儿尿路梗阻绵羊模型中的表达。类似于人类多囊性发育不良肾和小鼠多囊肾。在囊肿上皮和发育不良的肾小管中，p38、ERK表达上调，JNK表达下调。少

项目成果

Awazu M., et al.: "MAP kinase in renal development"Nephrol Dial Transplant. (印刷中). (2002)

Awazu M. 等人：“肾发育中的 MAP 激酶”Nephrol Dial Transplant（正在出版）。

大森さゆ 他: "腎嚢胞性疾患におけるMAPキナーゼ"発達腎研究会誌. (印刷中). (2002)

Sayu Omori 等人：“肾囊肿病中的 MAP 激酶”，发育肾脏研究学会杂志（2002 年出版）。

飛彈麻里子 他: "腎発生におけるMAPキナーゼの役割"発達腎研究会誌. (印刷中).

Mariko Hijima 等人：“MAP 激酶在肾脏发育中的作用”，发育肾脏研究学会杂志（正在出版）。

粟津緑: "Annual Review腎臓2002"Multicystic dysplastic kidney とMAPKSのdysregulation(印刷中). (2002)

Midori Awazu：“2002 年肾脏年度回顾”多囊性发育不良性肾脏和 MAPKS 失调（印刷中）。

大森 さゆ 他: "嚢胞性腎疾患におけるMAPキナーゼ"発達腎研究会誌. (印刷中). (2002)

Sayu Omori 等人：“囊性肾病中的 MAP 激酶”，发育肾脏研究学会杂志（正在出版）（2002 年）。