title: Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis.
abstract: 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.
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2584, USA.
authors.forename: Masashi
authors.initials: M
authors.lastname: Nishida
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Fujinaka
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.forename: James
authors.initials: J
authors.lastname: Price
authors.forename: Valentina
authors.initials: V
authors.lastname: Kon
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Davidson
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.forename: Toshio
authors.initials: T
authors.lastname: Homma
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yoshida
authors.forename: Iekuni
authors.initials: I
authors.lastname: Ichikawa
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000502:physiology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D005355:Fibrosis; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism*; D016897:Respiratory Burst; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014517:Ureteral Obstruction
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; C508961:Tgfb1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D020778:Matrix Metalloproteinase 2