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Am J Physiol Regul Integr Comp Physiol 283: R757-R767, 2002. First published May 16, 2002; doi:10.1152/ajpregu.00098.2002
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Vol. 283, Issue 3, R757-R767, September 2002

Antihypertensive effects of chronic anti-TGF-beta antibody therapy in Dahl S rats

Annette J. Dahly1, Kimberly M. Hoagland1, Averia K. Flasch1, Sharda Jha2, Steven R. Ledbetter2, and Richard J. Roman1

1 Medical College of Wisconsin, Department of Physiology, Milwaukee, Wisconsin 53226; and 2 Genzyme Corporation, Framingham, Massachusetts 01701

This study examined the role of transforming growth factor-beta (TGF-beta ) in the development of hypertension and renal disease in 9-wk-old male Dahl salt-sensitive (Dahl S) rats fed an 8% NaCl diet for 3 wk. The rats received an intraperitoneal injection of a control or an anti-TGF-beta antibody (anti-TGF-beta Ab) every other day for 2 wk. Mean arterial pressure was significantly lower in Dahl S rats treated with anti-TGF-beta Ab (177 ± 3 mmHg, n = 12) than in control rats (190 ± 4 mmHg, n = 17). Anti-TGF-beta Ab therapy also reduced proteinuria from 226 ± 20 to 154 ± 16 mg/day. Renal blood flow, cortical blood flow, and creatinine clearance were not significantly different in control and treated rats; however, medullary blood flow was threefold higher in the treated rats than in the controls. Despite the reduction in proteinuria, the degree of glomerulosclerosis and renal hypertrophy was similar in control and anti-TGF-beta Ab-treated rats. Renal levels of TGF-beta 1 and -beta 2, alpha -actin, type III collagen, and fibronectin mRNA decreased in rats treated with anti-TGF-beta Ab. To examine whether an earlier intervention with anti-TGF-beta Ab would confer additional renoprotection, these studies were repeated in a group of 6-wk-old Dahl S rats. Anti-TGF-beta Ab therapy significantly reduced blood pressure, proteinuria, and the degree of glomerulosclerosis and renal medullary fibrosis in this group of rats. The results indicate that anti-TGF-beta Ab therapy reduces blood pressure, proteinuria, and the renal injury associated with hypertension.

blood pressure; proteinuria; glomerulus; kidney; renal hemodynamics; glomerulosclerosis; transforming growth factor-beta


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