Individual differences in renal ACE activity in healthy rats predict susceptibility to adriamycin-induced renal damage.
BACKGROUND
In man, differences in angiotensin-converting enzyme (ACE) levels, related to ACE (I/D) genotype, are associated with renal prognosis. This raises the hypothesis that individual differences in renal ACE activity are involved in renal susceptibility to inflicted damage. Therefore, we studied the predictive effect of renal ACE activity for the severity of renal damage induced by a single injection of adriamycin in rats.


METHODS
Renal ACE activity (Hip-His-Leu cleavage by cortical homogenates) was determined by renal biopsy in 27 adult male Wistar rats. After 1 week of recovery, proteinuria was induced by adriamycin [1.5 mg/kg intravenously (i.v.) n = 18; controls, saline i.v. n = 9]. Proteinuria was measured every 2 weeks. After 12 weeks, rats were sacrificed and their kidneys harvested.


RESULTS
As anticipated, adriamycin elicited nephrotic range proteinuria, renal interstitial damage and mild focal glomerulosclerosis. Baseline renal ACE positively correlated with the relative rise in proteinuria after adriamycin (r = 0.62, P<0.01), renal interstitial alpha-smooth muscle actin (r = 0.49, P<0.05), interstitial macrophage influx (r = 0.56, P<0.05), interstitial collagen III (r = 0.53, P<0.05), glomerular alpha-smooth muscle actin (r = 0.74, P<0.01) and glomerular desmin (r = 0.48, P<0.05). Baseline renal ACE did not correlate with focal glomerulosclerosis (r = 0.22, NS). In controls, no predictive values for renal parameters were observed.


CONCLUSIONS
Individual differences in renal ACE activity predict the severity of adriamycin-induced renal damage in this outbred rat strain. This supports the assumption that differences in renal ACE activity predispose to a less favourable course of renal damage.
Rook
Mieneke
M
Department of Nephrology, Groningen University Medical Center, Groningen, The Netherlands.
Lely
A Titia
AT
Kramer
Andrea B
AB
van Goor
Harry
H
Navis
Gerjan
G
D000818:Animals; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004317:Doxorubicin / Q000633:toxicity*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D009401:Nephrosis / Q000139:chemically induced / Q000473:pathology*; D007703:Peptidyl-Dipeptidase A / Q000032:analysis / Q000378:metabolism*; D011237:Predictive Value of Tests; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric
D004317:Doxorubicin; D007703:Peptidyl-Dipeptidase A