Captopril prevents nephropathy in HIV-transgenic mice.
Transgenic mice (T26) bearing the envelope, regulatory, and accessory genes of HIV- I develop renal disease resembling human HIV-associated nephropathy (HIVAN). Effects of vehicle (VEH) and the angiotensin-converting enzyme inhibitor captopril (CAP) were examined in wild-type (WT) or T26 mice treated from 7 to 100 d of age. Mortality was lower in CAP T26 mice (30 mg/kg: 8%; 100 mg/kg: 12%) than VEH T26 mice (52%). The urinary protein/creatinine ratio was increased in VEH T26 mice (19.5+/-7.60) versus WT mice (6.1+/-0.83), but not in low-dose (7.3+/-0.94) or high-dose (8.2+/-1.02) CAP T26 mice. Blood urea nitrogen was higher in VEH T26 mice (52+/-16.2 mg/dl) than VEH WT mice (24+/-0.8). Blood urea nitrogen was also elevated in CAP WT (high dose: 43+/-2.1 mg/dl) and T26 mice (high dose: 42+/-2.4 mg/dl). Glomerular injury was higher in VEH T26 mice (6.8+/-0.58) than VEH WT mice (0.2+/-0.08) or CAP T26 mice (low dose: 1.1+/-0.17; high dose: 0.7+/-0.13). Tubulointerstitial injury was also greater in VEH T26 mice (1.1+/-0.10) than VEH WT mice (0.2+/-0.08) or CAP T26 mice (low dose: 0.4+/-0.10; high dose: 0.3+/-0.10). These data validate recent nonrandomized studies of captopril in HIV-infected patients, and suggest that an angiotensin-converting enzyme substrate is an important mediator in HIVAN. A randomized placebo-controlled trial of captopril in HIVAN may be warranted.
Division of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Princeton, New Jersey 08543, USA.
J E
JE
Bird
S K
SK
Durham
M R
MR
Giancarli
P H
PH
Gitlitz
D G
DG
Pandya
D M
DM
Dambach
M M
MM
Mozes
J B
JB
Kopp
D016263:AIDS-Associated Nephropathy / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002216:Captopril / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005814:Genes, Viral; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011507:Proteinuria / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood / Q000235:genetics
D000806:Angiotensin-Converting Enzyme Inhibitors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D002216:Captopril