Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis

被引:115
作者
Nishida, M
Fujinaka, H
Matsusaka, T
Price, J
Kon, V
Fogo, AB
Davidson, JM
Linton, MF
Fazio, S
Homma, T
Yoshida, H
Ichikawa, I [1 ]
机构
[1] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA
[2] Tokai Univ, Sch Med, Dept Pediat, Isehara, Kanagawa 25911, Japan
[3] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA
[4] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA
关键词
D O I
10.1172/JCI200215045
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
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 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.
引用
收藏
页码:1859 / 1868
页数:10
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