J Pharmacol Toxicol 41 (1999) 69–73 1056-8719/99/$ – see front matter © 1999 Elsevier Science Inc. All rights reserved. PII: S1056-8719(99)00015-5 Dose of doxorubicin determines severity of renal damage and responsiveness to ACE-inhibition in experimental nephrosis Frits H. Wapstra a , Harry van Goor b , Paul E. de Jong a , Gerjan Navis a,c, *, Dick de Zeeuw a,c Groningen Institute of Drug Studies (GIDS*), Departments of a Medicine, Division of Nephrology, b Pathology, and c Clinical Pharmacology, State University, University Hospital, Hanzeplein 1, 9713 GZ Groningen, The Netherlands Received January 14, 1999; revised and accepted March 31, 1999 Abstract Nephrosis induced by doxorubicin (adriamycin) is an experimental model of glomerulosclerosis with relative stable proteinuria which is commonly used for pharmacological intervention studies. It is induced by a single or a double dose of doxorubicin, with doses that vary considerably among investigators from 2 to 7.5 mgkg. Intervention studies with ACE-inhibitors in this model have provided conflicting results. We hypothesized that these discrepancies might be due to different properties of the doxorubicin model, related to the dose of doxorubicin used to induce proteinuria. We tested this hypothesis by inducing doxorubicin nephrosis with 1, 2 and 3 mgkg, and evaluat- ing the response to intervention with lisinopril. The 1-mgkg doxorubicin dose did not induce significant proteinuria. The 2- and the 3-mg kg dose resulted in a proteinuria of 684215 mg24 h and 736277 mg24 h 6 weeks after induction, respectively (MeanSD). Treatment with lisinopril 2 mgkgday reduced proteinuria to 160170 mg24 h(p0.01) in the 2-mgkg doxorubicin group, whereas in the 3-mgkg doxorubicin group, proteinuria did not respond to lisinopril (529264 mg24 h). In time control rats, proteinuria remained stable. Renal damage developed in both time control groups, with a glomerulosclerosis score of 2922 in the 2-mgkg group and 8441 in the 3-mgkg doxorubicin group. Lisinopril resulted in a significantly lower glomerulosclerosis score in the 2-mg kg doxorubicin group only (1615, p0.05), whereas the 3-mgkg group showed no significant reduction (5629, NS). In conclusion, the dose of doxorubicin used to induce nephrosis is an important determinant not only of the severity of the ensuring renal damage, but also of the response to intervention by ACE-inhibition. These findings have an impact on the interpretation of intervention studies in this model. © 1999 Elsevier Science Inc. Keywords: Adriamycin; doxorubicin; nephrosis; ACE-inhibition; lisinopril; glomerulosclerosis; proteinuria; blood pressure 1. Introduction In the rat, doxorubicin (adriamycin) induced changes in glomerular capillary permeability resulting in a nephrotic syndrome without hypertension and without marked early renal function loss (Bertani et al., 1988; Grond et al., 1988; Weening et al., 1990; Hall et al., 1986). Proteinuria gradu- ally increases until 4–8 weeks after disease induction and remains relatively stable thereafter. After several weeks, glomerular sclerotic lesions can be detected (Bertani et al., 1982). These features render doxorubicin nephrosis an ex- perimental model well-fitted to investigate the role of pro- teinuria in the pathogenesis of glomerulosclerosis (Okuda et al., 1986). Accordingly, the doxorubicin model is used by several laboratories not only to elucidate the mechanisms of progressive renal function loss (Tamaki et al., 1994; Paczek et al., 1992; Okuda et al., 1987; Bustos et al., 1996), but also to investigate the effects of renoprotective intervention ther- apy (Beukers et al., 1988; Scholey et al., 1989; Nagashima et al., 1995; Okasora et al., 1982). The dose of doxorubicin used to induce renal disease varies between different laboratories. In general, 2 to 5 mg kg is used, but a dose of 7.5 mg has also been reported. The impact of these differences in dosage on the specific fea- tures of this model, however, is unknown. We recently re- ported on the antiproteinuric effect of lisinopril in doxorubi- cin nephrosis (Wapstra et al., 1996). In contrast with studies on the effects of ACE-inhibition in the doxorubicin model by other investigators, the ACE-inhibitor appeared highly effective in lowering proteinuria. In this study, we used 2 mgkg doxorubicin to induce renal disease, whereas the other studies used a dose of 3 mgkg or more. We hypothe- sized that the better response to ACE-inhibition in our study * Corresponding author. Gerjan Navis, MD, PhD Department of Neph- rology. Tel.: +31-50-3612621; fax: +31-50-3619310. E-mail: g.j.navis@ int.axg.nl * GIDS is a part of the Groningen Utrecht Institute for Drug Explora- tion (GUIDE)