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-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.
Nishida
Masashi
M
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2584, USA.
Fujinaka
Hidehiko
H
Matsusaka
Taiji
T
Price
James
J
Kon
Valentina
V
Fogo
Agnes B
AB
Davidson
Jeffrey M
JM
Linton
MacRae F
MF
Fazio
Sergio
S
Homma
Toshio
T
Yoshida
Hiroaki
H
Ichikawa
Iekuni
I
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
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