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

J Clin Invest. 2002 Dec;110(12):1859-68. doi: 10.1172/JCI15045.

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.

Publication types

  • Comment
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Collagen Type I
  • Collagen Type III
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin
  • Tgfb1 protein, mouse
  • Tissue Inhibitor of Metalloproteinase-1
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Matrix Metalloproteinase 2