title: Hypertension and renal injury in experimental polycystic kidney disease.
abstract: Hypertension and renal injury in experimental polycystic kidney disease.
  
  
  BACKGROUND
  Hypertension accelerates renal failure in autosomal dominant polycystic kidney disease (ADPKD), and evidence suggests a role for the renin-angiotensin system (RAS) in the functional and structural changes. To explore the hypothesis that RAS adaptations contribute to disease progression, we examined RAS activity and the long-term consequences of antihypertensive drugs, which suppress (enalapril) or stimulate (hydralazine) the RAS, in experimental polycystic kidney disease.
  
  
  METHODS
  Studies were conducted in male heterozygous cystic Han:SPRD rats (Cy/+) and in unaffected littermates (controls). In protocol 1, either angiotensin II (Ang II), enalaprilat, or saline vehicle was acutely infused into cystic and control rats, which were aged 10 to 12 weeks. The mean arterial pressure (MAP), glomerular filtration rate (GFR), and renal plasma flow (RPF) were measured at baseline and after an infusion of test substances. In protocol 2, cystic rats received chronic therapy with either enalapril, hydralazine, or no therapy for 10 to 12 weeks of age and then underwent renal function and RAS studies. In protocol 3, similar cohorts were followed for 40 weeks to assess the effects of therapy on blood pressure, proteinuria, serum creatinine, RAS parameters, and renal morphology.
  
  
  RESULTS
  In protocol 1, cystic rats had massive kidneys, slightly elevated blood pressure, and profound renal vasoconstriction and reduced GFR. Ang II induced similar changes in MAP and renal function in control and cystic rats. Enalaprilat induced little effect on MAP but more striking increases in GFR and RPF in cystic rats. In protocol 2, at 10 weeks of age, enalapril was superior in preserving renal function, but neither drug limited the expansion of the tubulointerstitium. In protocol 3, at 40 weeks of age, both drugs ameliorated the increase in serum creatinine, although only enalapril reduced proteinuria and kidney size.
  
  
  CONCLUSIONS
  In polycystic rats, acute RAS suppression markedly ameliorates renal dysfunction. However, although chronic enalapril and hydralazine protect against the loss of renal function, only enalapril limits renal growth and proteinuria, and neither significantly limits tubulointerstitial fibrosis. The long-term studies give clear support to the importance of blood pressure control, per se, but only partial support to the importance of the particular agent used. As in clinical studies, angiotensin-converting enzyme inhibition may be less beneficial in ADPKD than in renal diseases characterized by predominant glomerular injury.
authors.affiliation: Department of Medicine, Oregon Health Sciences University, and Medical Service, Portland VA Medical Center, Portland, Oregon, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Kennefick
authors.forename: M A
authors.initials: MA
authors.lastname: Al-Nimri
authors.forename: T T
authors.initials: TT
authors.lastname: Oyama
authors.forename: M M
authors.initials: MM
authors.lastname: Thompson
authors.forename: F J
authors.initials: FJ
authors.lastname: Kelly
authors.forename: J G
authors.initials: JG
authors.lastname: Chapman
authors.forename: S
authors.initials: S
authors.lastname: Anderson
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D004656:Enalapril / Q000494:pharmacology; D005355:Fibrosis; D006830:Hydralazine / Q000494:pharmacology; D006977:Hypertension, Renal / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications* / Q000188:drug therapy / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D006830:Hydralazine; D004656:Enalapril