Role of Bone Morphogenetic Protein on the development of the Glomerulus

骨形态发生蛋白对肾小球发育的作用

• 批准号: 14571039
• 负责人: MIYAZAKI Yoichi
• 金额: $ 1.86万
• 依托单位: Jikei University School of Medicine
• 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 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571039/
• 关键词: Bmp; mutants; Glomerulus; nephrin; noggin; mutans; Glomerulus

Our previous studies on Bmp4 heterozygous mutants (Bmp4 +/-) suggest that BMP4 may have a role not only for the earlier development of kidney and urinary tract, but for the morphogensis of glomerulus. In the present study, we have developed mutant mice (neph-nog Tg) in which noggin, an endogenous inhibitor for BMP4, is over-expressed only in the glomerular epithelial cells using 5.4-kb 5'-franking region of the nephrin gene. In situ hybridization for noggin mRNA showed the signal is seen only in the glomerular epithelial cells. The expression level varies in different neph-nog Tgs, whereas no appreciable signal is seen in the wild type mice. The mice carrying higher level of noggin expression showed immature glomerular tuft surrounded by enlarged Bowman's capusule, the phenotype similar to that seen in Bmp4 +/-. Analyses of the P0 and E16.5 mutant embryos revealed that the initial defect is seen in the formation of the glomerular tuft. Whereas the differentiation and morphogenesis of glomerular epithelial cell layer per se is not affected, the glomerulus lacks the mesangial cells, resulting in the formation of glomerular microanuerysm. These results indicates that BMP4 is essential for the development of glomerular tuft

我们之前对 Bmp4 杂合突变体 (Bmp4 +/-) 的研究表明，BMP4 可能不仅对肾脏和泌尿道的早期发育起作用，而且对肾小球的形态发生也起作用。在本研究中，我们开发了突变小鼠（neph-nog Tg），其中 noggin（BMP4 的内源性抑制剂）仅在肾小球上皮细胞中使用 nephrin 基因的 5.4-kb 5'-franking 区域过度表达。头蛋白 mRNA 的原位杂交显示该信号仅在肾小球上皮细胞中可见。不同 neph-nog Tgs 的表达水平有所不同，而在野生型小鼠中没有看到明显的信号。携带较高水平 noggin 表达的小鼠显示出不成熟的肾小球簇，周围有扩大的鲍曼囊，该表型与 Bmp4 +/- 中所见的表型相似。对 P0 和 E16.5 突变体胚胎的分析表明，最初的缺陷出现在肾小球簇的形成中。虽然肾小球上皮细胞层本身的分化和形态发生不受影响，但肾小球缺乏系膜细胞，导致肾小球微血管瘤的形成。这些结果表明 BMP4 对于肾小球簇的发育至关重要

项目成果

Kuwayama F, Miyazaki Y, Ichikawa I: "Embryogenesis of the congenital anomalies of the kidney and the urinary tract."Nephrology Dialysis and Transplantation. 17. 45-47 (2002)

Kuwayama F、Miyazaki Y、Ichikawa I：“肾脏和泌尿道先天性异常的胚胎发生。”肾脏病透析和移植。

Matsusaka T, Miyazaki Y, Ichikawa I: "The renin angiotensin system and kidney development."Annual Review of Physiology. 64. 551-561 (2002)

Matsusaka T、Miyazaki Y、Ichikawa I：“肾素血管紧张素系统和肾脏发育。”生理学年度评论。

Ichikawa I, Kuwayama F, Stephens ED, Miyazaki Y: "The ontogeny of CAKUT."Kidney International. (61). 889-898 (2002)

Ichikawa I、Kuwayama F、Stephens ED、Miyazaki Y：“CAKUT 的个体发育。”肾脏国际。

Miyazaki Y, Oshima K, Fogo A, Ichikawa I: "Evidence that bone morphogenetic protein 4 has multiple biological functions during kidney and urinary tract development."Kidney International. 63. 835-844 (2003)

Miyazaki Y、Oshima K、Fogo A、Ichikawa I：“骨形态发生蛋白 4 在肾脏和泌尿道发育过程中具有多种生物学功能的证据。”肾脏国际。

Ichikawa I, Kuwayama F, Stephens FD, Miyazaki Y: "The ontogeny of CAKUT."Kidney International. 61. 889-898 (2002)

Ichikawa I、Kuwayama F、Stephens FD、Miyazaki Y：“CAKUT 的个体发育。”肾脏国际。