TY - JOUR
T1 - Hypertension and renal injury in experimental polycystic kidney disease
AU - Kennefick, Thomas M.
AU - Al-Nimri, Muna A.
AU - Oyama, Terry T.
AU - Thompson, Michele M.
AU - Kelly, Francis J.
AU - Chapman, Justin G.
AU - Anderson, Sharon
N1 - Funding Information:
These studies were supported, in part, by grants from the Polycystic Kidney Research Foundation (S.A.), the Juvenile Diabetes Foundation (T.M.K.), and the National Institutes of Health (S.A.). We are grateful to Dr. Benjamin Cowley, University of Kansas Medical Center, for the gift of breeding pairs to start our Han:SPRD colony; to Dr. William M. Bennett, for helpful advice and encouragement; to Ms. Kristen M. Allison, for excellent technical assistance; and to Christopher L. Corless, M.D., Ph.D., for assistance with the histological sections. Portions of these studies have been published in abstract form (J Am Soc Nephrol 7:1583 and 1616, 1996; 8:374, 1997).
PY - 1999
Y1 - 1999
N2 - 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.
AB - 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.
KW - Angiotensin
KW - Hydralazine
KW - Interstitial fibrosis
KW - PKD
KW - Progressive renal disease
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U2 - 10.1046/j.1523-1755.1999.00783.x
DO - 10.1046/j.1523-1755.1999.00783.x
M3 - Article
C2 - 10594794
AN - SCOPUS:0033456256
SN - 0085-2538
VL - 56
SP - 2181
EP - 2190
JO - Kidney International
JF - Kidney International
IS - 6
ER -