Role of angiotensin and bcl-2 on renal organogenesis.

血管紧张素和 bcl-2 对肾器官发生的作用。

• 批准号: 07670231
• 负责人: NAGATA Michio
• 金额: $ 1.47万
• 依托单位: Unversity of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670231/
• 关键词: Bcl-2; Renin angiotensin svstem; Kidney; Knock-out mice; Angiotensinogen; Metanephric culture; Nephrogenesis; Development; nephrogeuesis; avgioteusinogen; gene targeting; hypoplastic kiduey

Role of angiotensin and bcl-2 on renal organogenesis was investigated using recently established angiotensinogen and bcl-2 gene desrupted mice.1)Angiotensin deficient mice.Embryonic kidneys in Atg -/- mice from E13 to E18 exhibited active nephrogenesis, as also observed in Atg +/- mice and Atg +/+ mice. Futhermore, metanephroi harvested at E12 from Atg -/- embryos showed similar branching morphogenesis of ureteric bud and tubulogenesis as metanephroi from Atg -/- embryos grown with exogenous angiotensin II.In newborn Atg -/- mice, we observed unifrom dilatation of the pelvis accompanied by a coarse medulla. Hydronephrosis continued and renal papillae underwent atrophy for the 4 weeks after birth. Moreover, hickening of vascular walls as little as two weeks after birth was impressive. in situ hybridization and immunohistochemistry demonctrated that expression of renin mRNA became prominent in parallel with hyperplasia of VSMC,as well as recruitment of renin protein. In conclusion, the r … More enin-angiotensin system appears not be essential for nephrogenesis in vivo. Furthermore, hyperplasia of VSMC and expression of the smoothmuscle phenotype in the mesangium are inducible even in the absence of angiotensin II,with hypotension, in vivo.2)bcl-2 deficient miceExtensive apoptosis occurred during abnormal nephrogenesis in bcl-2 deficient mice. In bcl-2 -/- mice, initial induction of nephron was detected by embryonic day 13 (E-13) as normal. Then, apoptotic cells became five times more frequent at E-13 to E-16 with a significant reduction (1/5) in nephron number at E-17 to E-19 in bcl-2 -/- mice compared to bcl-2 +/+ mice. No morphological difference was evident between bcl-2 +/- mice and bcl-2 +/+ mice by morphometry. Apoptotic cells were found mainly among the mesenchyme and less frequently in tubuli. Little apoptosis among ureteric buds was noted. In bcl-2 -/- mice at E-17 to E-19, inactive branching and insufficient convolution of ureteric buds were accompanied by fulminant apoptosis in the mesenchyme. Neonatal bcl-2 -/- mice lacked the nephrogenic zone, exhibiting renal hypoplasia. Thus, bcl-2 seems to inhibit apoptosis in renal stem cells during the induction of nephron in vivo. Less

用新建立的血管紧张素原和bcl-2基因破坏小鼠研究了血管紧张素和bcl-2在肾脏器官发生中的作用。1)血管紧张素缺陷小鼠。从E13到E18， Atg -/-小鼠的胚胎肾脏表现出活跃的肾形成，在Atg +/-小鼠和Atg +/+小鼠中也观察到。此外，在E12时从Atg -/-胚胎中收获的后肾与外源血管紧张素II培养的Atg -/-胚胎的后肾在输尿管芽和小管发生方面表现出相似的分支形态发生。在新生的Atg -/-小鼠中，我们观察到骨盆均匀扩张并伴有粗髓质。出生后4周，肾积水持续，肾乳头萎缩。此外，出生后两周的血管壁增厚令人印象深刻。原位杂交和免疫组织化学表明，肾素mRNA的表达与VSMC的增生以及肾素蛋白的募集并行。综上所述，r…More enin-angiotensin系统似乎不是体内肾形成所必需的。此外，即使在体内没有血管紧张素II并伴有低血压的情况下，系膜内VSMC的增生和平滑肌表型的表达也是可诱导的。2)bcl-2缺陷小鼠在bcl-2缺陷小鼠异常肾形成过程中发生了广泛的细胞凋亡。bcl-2 -/-小鼠在胚胎第13天（E-13）检测肾素的初始诱导。然后，与bcl-2 +/+小鼠相比，bcl-2 -/-小鼠在E-13至E-16的凋亡细胞频率增加了5倍，在E-17至E-19的肾单位数量显著减少（1/5）。bcl-2 +/-小鼠与bcl-2 +/+小鼠形态测定无明显差异。凋亡细胞以间质细胞为主，小管细胞较少。输尿管芽细胞凋亡少。bcl-2 -/-小鼠在E-17 ~ E-19时，输尿管芽分支失活和褶曲不足伴间质暴发性凋亡。新生bcl-2 -/-小鼠缺乏肾源区，表现为肾发育不全。因此，bcl-2似乎在体内抑制肾干细胞在诱导肾元过程中的凋亡。少

项目成果

Nagata M,Nakauchi, H,Nakayama K,Nakayama K,Loh D,Watanabe T: "Apoptosis during an early stage of nephogenesis induces renal hypoplasia in bcl-2 deficient mice." Am J Path. 148. 1601-1611 (1996)

Nagata M、Nakauchi、H、Nakayama K、Nakayama K、Loh D、Watanabe T：“肾发生早期的细胞凋亡会诱导 bcl-2 缺陷小鼠的肾脏发育不全。”

Nagata M,Watanabe T: "Podocytes in metanephric organ culture express characteristic in vivo phenotypes" Histochemistry & Cell Biol. (in press). (1997)

Nagata M，Watanabe T：“后肾器官培养中的足细胞表达特征性体内表型”组织化学

Michio Nagata: "Nephrogenesis and renovascular development in angiotensinogen deficient mice." Lab Invest. 75. 745-753 (1996)

Michio Nagata：“血管紧张素原缺乏小鼠的肾发生和肾血管发育。”

M. Nagata,et. al.: "Macrophapes in Childhood ISA Nephropatty" Kiduey Iuternational. 48. 527-535 (1995)

M. Nagata 等。

M. Nagata: "Mitoxs and the preseuce of binucleated cells amovy glomenlar Podocyte in cliseased human kidueys" Nephron. 70. 68-71 (1995)

M. Nagata：“线粒体和双核细胞的前体，在关闭的人类肾小球中肾小球足细胞”肾单位。