Angiotensin-converting enzyme inhibition attenuates proteinuria and renal TGF-beta 1 mRNA expression in rats with chronic renal disease.
Evidence suggests that transforming growth factor beta 1 (TGF-beta 1), a multifunctional cytokine, induces renal extracellular matrix production and glomerular hypertrophy. The aim of the present study was to investigate the effect of captopril on the expression of TGF-beta 1 mRNA in a rat model of chronic renal failure: five-sixths nephrectomy. Chronic renal disease was induced by removal of the right kidney and ligation of three blood vessels supplying the left kidney. Sham-operated animals were used as controls. RNA was extracted from the viable remnant kidney of rats 1 day and 1 and 2 weeks following five-sixths nephrectomy and from the kidneys of rats who underwent sham surgery. TGF-beta 1 mRNA was induced within 24 h of partial nephrectomy, similar to that reported for early-onset genes. Subsequently, TGF-beta 1 mRNA expression continued to increase over the next 2-4 weeks. The upregulation of TGF-beta 1 correlated with the degree of proteinuria. Both the increase in TGF-beta 1 mRNA and proteinuria were abrogated by captopril treatment. In addition, no change in expression of ALK-5 or type II TGF-beta receptors following five-sixths nephrectomy was observed. These data suggest that captopril may protect against development of glomerulosclerosis and proteinuria by reducing TGF-beta 1 expression and hence matrix production.
Department of Renal and Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
S M
SM
Ali
N J
NJ
Laping
T A
TA
Fredrickson
L C
LC
Contino
B a
Ba
Olson
K
K
Anderson
D P
DP
Brooks
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D002216:Captopril / Q000494:pharmacology*; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000601:surgery; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000652:urine*; D009392:Nephrectomy; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects; D011507:Proteinuria / Q000652:urine*; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000187:drug effects* / Q000235:genetics
D000806:Angiotensin-Converting Enzyme Inhibitors; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D002216:Captopril; D007703:Peptidyl-Dipeptidase A