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

Nishida M, Fujinaka H, Matsusaka T, Price J, Kon V, Fogo AB, Davidson JM, Linton MF, Fazio S, Homma T, Yoshida H, Ichikawa I
J Clin Invest. 2002 110 (12): 1859-68

PMID: 12488436 · PMCID: PMC151648 · DOI:10.1172/JCI15045

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(I) 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.

MeSH Terms (24)

Animals Bone Marrow Transplantation Cell Movement Collagen Type I Collagen Type III Extracellular Matrix Fibrosis Hematopoietic Stem Cells Kidney Kidney Diseases Macrophages Male Matrix Metalloproteinase 2 Mice Mice, Inbred C57BL Mice, Knockout Phagocytosis Receptor, Angiotensin, Type 1 Receptors, Angiotensin Respiratory Burst Tissue Inhibitor of Metalloproteinase-1 Transforming Growth Factor beta Transforming Growth Factor beta1 Ureteral Obstruction

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