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

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。诱导单侧输尿管梗阻(UUO)后14天，Agtrl基因缺失的野生型小鼠(Agtrl^&lt；-/-&gt；)发生严重的间质纤维化，间质巨噬细胞少于Agtrl^&lt；+/+&gt；。UUO后第5天未观察到上述差异。促纤维化基因--包括转化生长因子-β-1、α-1(I)胶原和α-1(III)胶原--在移植Agtrl^&lt；-/-&gt；的小鼠肾脏中的表达在第14天显著高于Agtrl^&lt；+/+&gt；的小鼠，但在UUO的第5天则不明显。患有Agtr1^&lt；-/-&gt；骨髓的小鼠的特征是骨髓中外周血单核细胞和巨噬细胞前体细胞数量减少。体内试验显示，Agtr1^&lt；-/-&gt；巨噬细胞的吞噬能力显著受损。在体内用氯沙坦治疗Agtr1^&lt；+/+&gt；小鼠，可将Agt1^&lt；+/+&gt；巨噬细胞的吞噬能力降低到与Agtrl^&lt；-/-&gt；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Agtrl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 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.