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 (α) (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.

[1]  H. Jin,et al.  Angiotensin type-1 receptor blockade with losartan increases insulin sensitivity and improves glucose homeostasis in subjects with type 2 diabetes and nephropathy. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[2]  R. Gomer,et al.  Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice , 2006, Proceedings of the National Academy of Sciences.

[3]  S. Kaneko,et al.  Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis , 2006, Proceedings of the National Academy of Sciences.

[4]  R. Schwabe,et al.  Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. , 2006, Journal of hepatology.

[5]  K. Chayama,et al.  Anti-fibrogenic function of angiotensin II type 2 receptor in CCl4-induced liver fibrosis. , 2006, Biochemical and biophysical research communications.

[6]  Z. Su,et al.  Angiotensin-(1-7) inhibits angiotensin II-stimulated phosphorylation of MAP kinases in proximal tubular cells. , 2006, Kidney international.

[7]  Christopher J. Parsons,et al.  Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct–ligated rats , 2005, Hepatology.

[8]  Charles E McCulloch,et al.  Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. , 2004, The New England journal of medicine.

[9]  R. Chen,et al.  Possible Inhibition of Focal Cerebral Ischemia by Angiotensin II Type 2 Receptor Stimulation , 2004, Circulation.

[10]  M. Burdick,et al.  Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. , 2004, The Journal of clinical investigation.

[11]  K. Matsushima,et al.  Blockade of CCR2 ameliorates progressive fibrosis in kidney. , 2004, The American journal of pathology.

[12]  YoshihiroSuematsu,et al.  Protective Effects of Endogenous Adrenomedullin on Cardiac Hypertrophy, Fibrosis, and Renal Damage , 2004 .

[13]  Y. Suematsu,et al.  Protective effects of endogenous adrenomedullin on cardiac hypertrophy, fibrosis, and renal damage. , 2004, Circulation.

[14]  Yasunori Iwata,et al.  Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. , 2004, Journal of the American Society of Nephrology : JASN.

[15]  Shawn Cowper,et al.  Circulating fibrocytes: collagen-secreting cells of the peripheral blood. , 2004, The international journal of biochemistry & cell biology.

[16]  K. Nakao,et al.  Angiotensin II-induced ventricular hypertrophy and extracellular signal-regulated kinase activation are suppressed in mice overexpressing brain natriuretic peptide in circulation. , 2003, Hypertension research : official journal of the Japanese Society of Hypertension.

[17]  M. Pfeffer,et al.  Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme , 2003, The Lancet.

[18]  R. Kalluri,et al.  BMP-7 counteracts TGF-β1–induced epithelial-to-mesenchymal transition and reverses chronic renal injury , 2003, Nature Medicine.

[19]  N. Dusetti,et al.  Evidence of CXC, CC and C chemokine production by lymphatic endothelial cells , 2003, Immunology.

[20]  R. Chen,et al.  Role of Angiotensin II–Regulated Apoptosis Through Distinct AT1 and AT2 Receptors in Neointimal Formation , 2002, Circulation.

[21]  E. Neilson,et al.  Evidence that fibroblasts derive from epithelium during tissue fibrosis. , 2002, The Journal of clinical investigation.

[22]  V. Praloran,et al.  Angiotensin II That Reduces the Colony‐Forming Ability of Hematopoietic Progenitors in Serum Free Medium Has an Inverse Effect in Serum‐Supplemented Medium , 2002, Stem cells.

[23]  M. Iwai,et al.  Roles of Angiotensin II Type 2 Receptor Stimulation Associated With Selective Angiotensin II Type 1 Receptor Blockade With Valsartan in the Improvement of Inflammation-Induced Vascular Injury , 2001, Circulation.

[24]  J. Egido,et al.  Angiotensin II and renal fibrosis. , 2001, Hypertension.

[25]  R. Bucala,et al.  Peripheral Blood Fibrocytes: Differentiation Pathway and Migration to Wound Sites1 , 2001, The Journal of Immunology.

[26]  E. Schiffrin,et al.  Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. , 2000, Pharmacological reviews.

[27]  C. Chatziantoniou,et al.  Angiotensin II Activates Collagen I Gene Through a Mechanism Involving the MAP/ER Kinase Pathway , 2000, Hypertension.

[28]  M. Ushio-Fukai,et al.  Reactive oxygen species as mediators of angiotensin II signaling , 2000, Regulatory Peptides.

[29]  K. Rodgers,et al.  Effect of Angiotensin II on Hematopoietic Progenitor Cell Proliferation , 2000, Stem cells.

[30]  D. Erlinge,et al.  Angiotensin II type 1 receptors stimulate protein synthesis in human cardiac fibroblasts via a Ca2+-sensitive PKC-dependent tyrosine kinase pathway. , 2000, Acta physiologica Scandinavica.

[31]  K. Nath.  The tubulointerstitium in progressive renal disease. , 1998, Kidney international.

[32]  T. Inagami,et al.  Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. , 1998, Kidney international.

[33]  R. Bucala,et al.  Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes. , 1998, Journal of immunology.

[34]  K. Catt,et al.  Angiotensin receptors and their antagonists. , 1996, The New England journal of medicine.

[35]  S. El-Dahr,et al.  Sequential changes in renal expression of renin-angiotensin system genes in acute unilateral ureteral obstruction. , 1995, Kidney international.

[36]  R. Bucala,et al.  Circulating Fibrocytes Define a New Leukocyte Subpopulation That Mediates Tissue Repair , 1994, Molecular medicine.

[37]  S. Kaneko,et al.  Lymphocyte migration to the kidney , 2006 .

[38]  R. Badolato,et al.  Lymphocyte Trafficking in Health and Disease , 2006 .

[39]  R. Chen,et al.  Regulation of collagen synthesis in mouse skin fibroblasts by distinct angiotensin II receptor subtypes. , 2004, Endocrinology.

[40]  Teven,et al.  EFFECTS OF LOSARTAN ON RENAL AND CARDIOVASCULAR OUTCOMES IN TYPE 2 DIABETES AND NEPHROPATHY EFFECTS OF LOSARTAN ON RENAL AND CARDIOVASCULAR OUTCOMES IN PATIENTS WITH TYPE 2 DIABETES AND NEPHROPATHY , 2001 .

[41]  M. Nieminen,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group , 2022 .