Effect of combination therapy with enalapril and the TGF-beta antagonist 1D11 in unilateral ureteral obstruction.
In unilateral ureteral obstruction (UUO), the kidney is characterized by increased fibrosis and apoptosis. Both transforming growth factor-beta (TGF-beta) and ANG II have been implicated, and ANG II may mediate its effects through TGF-beta. Previous studies demonstrated amelioration of renal damage when either TGF-beta or ANG II has been individually targeted. In this study, we sought to determine whether combining 1D11 (monoclonal antibody to TGF-beta) 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-beta expression (real-time PCR and tubular localization with immunohistochemistry)]. UUO was found to induce fibrosis, apoptosis, macrophage infiltration, and TGF-beta 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.
El Chaar
Maher
M
Dept. of Urology, Weill Cornell Medical College, Box 94, 1300 York Ave., New York, NY 10021, USA.
Chen
Jie
J
Seshan
Surya V
SV
Jha
Sharda
S
Richardson
Ingride
I
Ledbetter
Steven R
SR
Vaughan
E D
ED
Poppas
Dix P
DP
Felsen
Diane
D
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D017209:Apoptosis / Q000502:physiology; D003094:Collagen / Q000096:biosynthesis; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000008:administration & dosage*; D005355:Fibrosis; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000276:immunology*; D014517:Ureteral Obstruction / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D004656:Enalapril; D003094:Collagen