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

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-β1, α1(I) collagen, and α1(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.