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This Article Full Text Full Text (PDF) All Versions of this Article: 292/4/F1291    most recent 00327.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by El Chaar, M. Articles by Felsen, D. Search for Related Content PubMed PubMed Citation Articles by El Chaar, M. Articles by Felsen, D.

Effect of combination therapy with enalapril and the TGF- antagonist 1D11 in unilateral ureteral obstruction

¹Institute for Pediatric Urology-Weill Cornell Medical College, ²Department of Pathology, Weill Cornell Medical College, New York, New York; and ³The Genzyme Corporation, Framingham, Massachusetts

Submitted 15 August 2005 ; accepted in final form 29 November 2006

In unilateral ureteral obstruction (UUO), the kidney is characterized by increased fibrosis and apoptosis. Both transforming growth factor- (TGF-) and ANG II have been implicated, and ANG II may mediate its effects through TGF-. Previous studies demonstrated amelioration of renal damage when either TGF- or ANG II has been individually targeted. In this study, we sought to determine whether combining 1D11 (monoclonal antibody to TGF-) and an ACE inhibitor, enalapril, would be more effective in UUO than either individual treatment, as has been shown in diabetic and glomerulonephritic models. Rats underwent UUO and were given either control monoclonal antibody, 1D11 or enalapril, or 1D11/enalapril combination, for 14 days. Kidneys were harvested and examined for fibrosis [trichrome; collagen (real-time PCR, Sircol assay) and fibroblast-specific protein expression (immunohistochemistry), apoptosis (TUNEL), macrophage infiltration (immunohistochemistry), and TGF- expression (real-time PCR and tubular localization with immunohistochemistry)]. UUO was found to induce fibrosis, apoptosis, macrophage infiltration, and TGF- expression in the obstructed kidney. Administration of either 1D11 or enalapril individually significantly decreased all these changes; when 1D11 and enalapril were combined, there was little additive effect, and the combination did not provide full protection against damage. The results demonstrate that, for the most part, combination therapy is not additive in UUO. This could be due to the continued presence of a physical obstruction or to biochemical differences between UUO and other renal disease models. Furthermore, it suggests that other targets may be amenable to pharmacological manipulation in UUO.

fibrosis; apoptosis; transforming growth factor-; converting enzyme inhibitor

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