Chronic blockade of angiotensin II action prevents glomerulosclerosis, but induces graft vasculopathy in experimental kidney transplantation.
Long-term renin-angiotensin system blockade is beneficial in a variety of renal diseases. This study examines the long-term (34 weeks) effects of the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor type I blocker L158,809 in the Fisher to Lewis rat model of chronic renal transplant failure. Treatment in allografted rats with lisinopril or L158,809 was initiated 10 days after transplantation, or at the time when proteinuria exceeded 50 mg/24 h. Untreated allografts and syngrafts served as controls. In contrast to syngrafts, untreated allografts developed proteinuria, hypercholesterolaemia, interstitial damage, and glomerulosclerosis. Lisinopril or L158,809 treatment in allografts starting at day 10 after transplantation completely prevented this, with the exception of interstitial damage, but this treatment also caused a reduction in blood pressure and renal function. Moreover, the intimal surface area of the renal arteries was dramatically increased in allografts treated with either lisinopril or L158,809 compared with untreated allografted rats. Treatment once proteinuria had developed was less effective in preventing glomerulosclerosis, but also caused less intimal expansion. Thus, chronic renin-angiotensin system blockade preserves glomerular morphology in the absence of proteinuria, but enhances intimal hyperplasia and reduces renal function in experimental transplantation. In view of these results, it should be questioned whether such treatment benefits renal transplant patients in the long term.
Smit-van Oosten
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A
Department of Pathology and Laboratory Medicine, University Hospital Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. a.van.oosten@path.azg.nl
Navis
G
G
Stegeman
C A
CA
Joles
J A
JA
Klok
P A
PA
Kuipers
F
F
Tiebosch
A T
AT
van Goor
H
H
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D005921:Glomerulonephritis / Q000517:prevention & control*; D006965:Hyperplasia / Q000139:chemically induced; D016030:Kidney Transplantation / Q000473:pathology*; D017706:Lisinopril / Q000627:therapeutic use; D008297:Male; D009842:Oligopeptides / Q000627:therapeutic use; D011183:Postoperative Complications / Q000517:prevention & control*; D011184:Postoperative Period; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012077:Renal Artery / Q000187:drug effects / Q000473:pathology; D012084:Renin-Angiotensin System / Q000187:drug effects; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D017706:Lisinopril