title: Vascular endothelin-1 gene expression and synthesis and effect on renal type I collagen synthesis and nephroangiosclerosis during nitric oxide synthase inhibition in rats.
abstract: BACKGROUND
  The progression of hypertension during NO deficiency is associated with renal vascular fibrosis due to increased extracellular matrix (mainly collagen I) formation. The purpose of the present study was to investigate whether endothelin-1 (ET-1) is involved in this pathophysiological process.
  
  
  RESULTS
  Treatment of rats for 4 weeks with the NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) 50 mg. kg-1. d-1 increased systolic blood pressure to 159+/-12 mm Hg. In animals treated with L-NAME, histological evaluation of renal sections revealed an increased formation of extracellular matrix (Masson's trichrome), and specifically of collagens (Sirius red). A part of this fibrosis was attributed to abnormal collagen I presence, because mRNA expression of the collagen I alpha1 chain (reverse transcription-polymerase chain reaction) and procollagen I formation (radioimmunoassay) were increased 3- and 2.5-fold, respectively, in the renal resistance vessels of hypertensive animals. In subsequent experiments, we examined whether ET-1 was involved in activation of collagen I formation. mRNA expression (RNase protection assay) of preproET-1 and ET-1 content (radioimmunoassay) were 10-fold and 3-fold increased, respectively, in renal microvessels of rats treated with L-NAME. Interestingly, in these vessels, ET-1 (immunostaining) was colocalized with sudanophilic lesions. Bosentan, an ET receptor antagonist (20 mg. kg-1. d-1), coadministered with L-NAME canceled the increased mRNA expression and synthesis of collagen I and attenuated the severity of renal vascular lesions without affecting L-NAME-induced high blood pressure.
  
  
  CONCLUSIONS
  These data demonstrate that ET-1 synthesis is increased in renal microvessels when NO production is suppressed. In this model of hypertension, ET-1 is a major activator of collagen I formation in renal resistance vessels and participates in the development of renal fibrosis without affecting systolic blood pressure.
authors.affiliation: INSERM U 489, Paris, France.
authors.forename: P L
authors.initials: PL
authors.lastname: Tharaux
authors.forename: C
authors.initials: C
authors.lastname: Chatziantoniou
authors.forename: D
authors.initials: D
authors.lastname: Casellas
authors.forename: L
authors.initials: L
authors.lastname: Fouassier
authors.forename: R
authors.initials: R
authors.lastname: Ardaillou
authors.forename: J C
authors.initials: JC
authors.lastname: Dussaule
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics*; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics* / Q000652:urine; D016232:Endothelins / Q000235:genetics; D005109:Extracellular Matrix / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D008833:Microcirculation / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009400:Nephrosclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011347:Procollagen / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000502:physiology*; D013599:Systole / Q000187:drug effects; D014158:Transcription, Genetic
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D011347:Procollagen; D011498:Protein Precursors; D012333:RNA, Messenger; D003094:Collagen; D019331:NG-Nitroarginine Methyl Ester