Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis
Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis
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DOI：
10.1172/jci200215045
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发表时间：
2002-12-01
影响因子：
15.9
通讯作者：
Ichikawa, I
中科院分区：
文献类型：
--
作者：
Nishida, M;Fujinaka, H;Ichikawa, I
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(Agtr1)的体内功能。单侧输尿管梗阻(UUO)后14天，Agtr1基因缺失骨髓(Agtr1(-/-))构建的野生型小鼠发生严重的间质纤维化，间质巨噬细胞数量少于Agtr1(+/+)骨髓构建的小鼠。UUO后第5天未观察到上述差异。在移植Agtr1(-/-)骨髓的受阻小鼠肾脏中，促纤维化基因--包括转化生长因子-β1、α1(L)胶原和α1(III)胶原的表达在UUO第14天显著高于Agtr1(+/+)小鼠，但在UUO的第5天则不明显。Agtr1(-/-)骨髓小鼠的特征是外周血单核细胞和骨髓中巨噬细胞前体细胞数量减少。体内实验显示，Agtr1(-/-)巨噬细胞的吞噬能力显著受损。在体内用氯沙坦治疗Agtr1(+/+)小鼠后，Agtr1(+/+)巨噬细胞的吞噬能力降低到与Agtr1(-/-)巨噬细胞相当的水平。因此，在尿路梗阻期间，骨髓来源的巨噬细胞上的Agtr1起到了保护肾实质结构的作用，这一功能部分依赖于它对吞噬功能的调节作用。
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 Agtr1 gene (Agtr1(-/-)) developed more severe interstitial fibrosis with fewer interstitial macrophages than those in mice reconstituted with Agtr1(+/+) marrow. These differences were not observed at day 5 of UUO. The expression of profibrotic genes - including TGF-beta1, alpha1(l) collagen, and alpha1(III) collagen - was substantially higher in the obstructed kidneys of mice with Agtr1(-/-) marrow than in those with Agtr1(+/+) 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 Agtr1(+/+) macrophages to a level comparable to that of Agtr1(-/-) macrophages. Thus, during urinary tract obstruction, the Agtr1 on bone marrow-derived macrophages functions to preserve the renal parenchymal architecture, and this function depends in part on its modulatory effect on phagocytosis.