Hypertension and renal injury in experimental polycystic kidney disease

Background. Hypertension accelerates renal failure in autosomal dominant po lycystic kidney disease (ADPKD), and evidence suggests a role for the renin -angiotensin system (RAS) in the functional and structural changes. To expl ore 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 e xperimental polycystic kidney disease. Methods. Studies were conducted in male heterozygous cystic Han:SPRD rats ( Cy/+) and in unaffected littermates (controls). In protocol 1, either angio tensin 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 (R PF) were measured at baseline and after an infusion of test substances. In protocol 2, cystic rats received chronic therapy with either enalapril, hyd ralazine, 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, s erum 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 ra ts. 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 w as superior in preserving renal function, but neither drug limited the expa nsion of the tubulointerstitium. In protocol 3, at 40 weeks of age, both dr ugs ameliorated the increase in serum creatinine, although only enalapril r educed proteinuria and kidney size. Conclusions. In polycystic rats, acute RAS suppression markedly ameliorates renal dysfunction. However, although chronic enalapril and hydralazine pro tect against the loss of renal function, only enalapril limits renal growth and proteinuria, and neither significantly limits tubulointerstitial fibro sis. The long-term studies give clear support to the importance of blood pr essure control, per se, but only partial support to the importance of the p articular agent used. As in clinical studies, angiotensin-converting enzyme inhibition may be less beneficial in ADPKD than in renal diseases characte rized by predominant glomerular injury.