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Effect of macrophages transferred with angiotensin II receptor gene on the evolution of renal fibrosis

转血管紧张素II受体基因的巨噬细胞对肾纤维化演变的影响

基本信息

批准号：
17591107
负责人：
NISHIDA Masashi
金额：
$ 2.24万
依托单位：
Kyoto Prefectural University 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：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591107/
关键词：
renal fibrosis macrophage unilateral ureteral obstruction angiotensin II type 1 receptor アンギオテンシンII type1レセプター MMP-2

项目摘要

We examined the in vivo function of the angiotensin II type 1 receptor (Agtr1) on macrophages in renal fibrosis. Fourteen days after the induction of unilateral ureteral obstruction (UUO), wild-type mice reconstituted with marrow lacking the Agtrl gene (Agtr1^<-/->) developed more severe interstitial fibrosis with fewer interstitial macrophages than those in mice reconstituted with Agtrl^<+/+> marrow. These differences were not observed at day 5 of UUO. The expression of profibrotic genes-including TGF-β1, α1(I) collagen, and α1(III) collagen-was substantially higher in the obstructed kidneys of mice with Agtr1^<-/->marrow than in those with Agtrl^<+/+> marrow at day 14 but not at day 5 of UUO. Mice with Agtr1^<-/->marrow were characterized by reduced numbers of peripheral-blood monocytes and macrophage progenitors in bone marrow. In vivo assays revealed a significantly impaired phagocytic capability in Agtr1^<-/->macrophages. In vivo treatment of Agtr1^<+/+> mice with losartan reduced phagocytic capability of Agt1^<+/+> macrophages to a level comparable to that of Agtrl^<-/->macrophages. Thus, during urinary tract obstruction, the Agtrl on bone marrow-derived macrophages functions to preserve the renal parenchymal architecture, and this function depends in part on its modulatory effect on phagocytosis.

我们研究了肾纤维化中巨噬细胞上血管紧张素II 1型受体（Agtr 1）的体内功能。在诱导单侧输尿管梗阻（UUO）后14天，用缺乏Agtr 1 ^<-/->基因的骨髓重建的野生型小鼠比用Agtr 1 ^<+/+>骨髓重建的小鼠发生更严重的间质纤维化，间质巨噬细胞更少。在UUO第5天未观察到这些差异。在UUO第14天，促纤维化基因（包括TGF-β1、α1（I）胶原和α1（III）胶原）的表达在带有Agtr 1 ^<-/->骨髓的小鼠阻塞肾脏中明显高于带有Agtrl^<+/+>骨髓的小鼠，但在UUO第5天则不然。具有Agtr 1 ^<-/->骨髓的小鼠的特征在于骨髓中外周血单核细胞和巨噬细胞祖细胞的数量减少。体内测定显示Agtr 1 ^<-/->巨噬细胞的吞噬能力显著受损。用氯沙坦在体内治疗Agtr 1 ^<+/+>小鼠使Agt 1 ^<+/+>巨噬细胞的吞噬能力降低到与Agt 1 ^<-/->巨噬细胞相当的水平。因此，在尿路梗阻期间，骨髓源性巨噬细胞上的Agglutinase起保护肾实质结构的作用，并且该功能部分取决于其对吞噬作用的调节作用。