title: Involvement of angiotensin II in cardiovascular and renal injury: effects of an AT1-receptor antagonist on gene expression and the cellular phenotype.
abstract: OBJECTIVE
  We investigated the effects of an angiotensin II type 1 (AT1)-receptor antagonist on experimental cardiac hypertrophy, vascular thickening and nephrosclerosis, in order to determine the involvement of this receptor in the development of cardiovascular and renal damage.
  
  
  METHODS
  Accumulating evidence indicates that various growth-related genes, growth factors and extracellular matrix components play a central part in the pathogenesis and development of cardiovascular and renal diseases, either by regulating cell growth and migration or by promoting tissue fibrosis.
  
  
  METHODS
  Stroke-prone spontaneously hypertensive rats were given candesartan cilexetil, a specific non-peptide AT1-receptor antagonist, for 10 weeks, and cardiac phenotypic and fibrosis-related gene expression and aortic and mesenteric arterial gene expressions were determined. Balloon-injured carotid arteries and deoxycorticosterone acetate (DOCA)-salt hypertensive rats were also similarly examined.
  
  
  RESULTS
  Treatment of hypertensive rats with an AT1-receptor antagonist led to the regression of cardiac hypertrophy, suppression of cardiac phenotypic changes to a fetal phenotype and an increase in fibrosis-related gene expression in the hypertrophied heart. Balloon injury-induced neointima formation in the rat carotid artery was prevented by the AT1-receptor antagonist, which was associated with the inhibition of the induction of proto-oncogenes such as c-fos, c-jun and Egr-1 and of increased fibronectin gene expression. Furthermore, the AT1-receptor antagonist prevented either the phenotypic modulation of glomerular cells or an increase in transforming growth factor-beta 1 expression in an experimental model of nephrosclerosis.
  
  
  CONCLUSIONS
  AT1-receptor antagonists in vivo potently inhibit the expression of the growth-related and extracellular matrix genes, as well as cellular phenotypic modulation. These molecular effects of the AT1-receptor antagonist may contribute to their protective effects on cardiovascular and renal diseases.
authors.affiliation: Department of Pharmacology, Osaka City University Medical School, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: H
authors.initials: H
authors.lastname: Iwao
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D009400:Nephrosclerosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology*; D013777:Tetrazoles
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005353:Fibronectins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C077793:candesartan cilexetil