title: The role of the renin-angiotensin system in cholesterol and puromycin mediated renal injury.
abstract: BACKGROUND
  Puromycin aminonucleoside (PAN) nephropathy is a widely studied model of glomerular sclerosis (GS) in the rat, and cholesterol feeding exacerbates the injury induced by PAN. The importance of the interaction of angiotensin II (Ang II) with the AT2 receptor is unclear. We investigated the role of the renin-angiotensin system, particularly with regard to AT1 and AT2 receptor dynamics, in PAN and cholesterol-mediated GS.
  
  
  METHODS
  Sprague-Dawley rats were given a 4% cholesterol diet (group II), subcutaneous PAN (group III), or a 4% cholesterol diet and PAN (group IV) and compared with a control group given PAN vehicle (group I). After 16 weeks, kidneys were harvested and tissue Ang II concentration, angiotensin-converting enzyme (ACE) activity, and ACE, AT1, and AT2 mRNA levels were determined.
  
  
  RESULTS
  Compared with control rats, proteinuria was significantly higher in groups II to IV. Kidney ACE activity and ACE mRNA levels in groups III and IV were 2- and 3-fold higher than in groups I and II, respectively. Kidney Ang II concentration also was increased in the experimental groups. Whereas kidney AT1 mRNA was significantly lower in groups III and IV, kidney AT2 mRNA was significantly increased in groups II to IV.
  
  
  CONCLUSIONS
  In these experimental models of GS, there is significant activation of the tissue-based renin-angiotensin system. Puromycin with and without cholesterol decreased the AT1 receptor mRNA and increased the AT2 receptor mRNA. Up-regulation of AT2 receptors may be important in ameliorating the proliferative effects of Ang II, which presumably occur through the AT1 receptor.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Ghosh
authors.forename: Domenic
authors.initials: D
authors.lastname: Sica
authors.forename: Anton C
authors.initials: AC
authors.lastname: Schoolwerth
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Quigg
authors.forename: Mark
authors.initials: M
authors.lastname: Haas
authors.forename: Itaf
authors.initials: I
authors.lastname: Fakhry
authors.forename: Todd W B
authors.initials: TW
authors.lastname: Gehr
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D004032:Diet; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology / Q000502:physiology; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria; D011692:Puromycin Aminonucleoside / Q000008:administration & dosage / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology*; D012598:Sclerosis
chemical_list: D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D011692:Puromycin Aminonucleoside; D002784:Cholesterol; D007703:Peptidyl-Dipeptidase A