The renin-angiotensin system contributes to renal fibrosis through regulation of fibrocytes.
BACKGROUND
The renin-angiotensin system is a major pathway in the pathogenesis of cardiovascular and renal diseases. Bone marrow-derived fibrocytes, which are dual positive for CD45 and type I collagen, are now considered to contribute to the pathogenesis of various fibrotic diseases. We hypothesized that fibrocytes might contribute to renal fibrosis by an angiotensin II dependent pathway.


RESULTS
In murine models of renal fibrosis, angiotensin II type 2 receptor (AT2R)-deficient mice, when compared with wild-type mice, showed increased renal fibrosis and fibrocyte infiltration with a concomitant upregulation of renal transcripts of procollagen type I (alpha) (COL1A1). Fibrocyte numbers in the bone marrow also were increased in AT2R-deficient mice. By contrast, pharmacological inhibition of angiotensin II type 1 receptor (AT1R) with valsartan reduced the degree of renal fibrosis and the number of fibrocytes in both the kidney and the bone marrow. In isolated human fibrocytes, inhibition of AT2R signaling increased the angiotensin II-stimulated expression of type I collagen, whereas inhibition of AT1R decreased collagen synthesis. These results suggest that AT1R/AT2R signaling may contribute to the pathogenesis of renal fibrosis by at least two mechanisms: by regulating the number of fibrocytes in the bone marrow, and by activation of fibrocytes.
Sakai
Norihiko
N
Disease Control and Homeostasis, Kanazawa University, Kanazawa, Japan.
Wada
Takashi
T
Matsushima
Kouji
K
Bucala
Richard
R
Iwai
Masaru
M
Horiuchi
Masatsugu
M
Kaneko
Shuichi
S
D000804:Angiotensin II / Q000097:blood / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001853:Bone Marrow / Q000502:physiology; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology* / Q000502:physiology*; D005355:Fibrosis; D006977:Hypertension, Renal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D007668:Kidney / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014662:Vasoconstrictor Agents / Q000097:blood / Q000494:pharmacology
C491224:Ccl12 protein, mouse; D054421:Chemokine CCL21; D024042:Collagen Type I; D018945:Monocyte Chemoattractant Proteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D053773:Transforming Growth Factor beta1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II