Antihypertensive effects of chronic anti-TGF-beta antibody therapy in Dahl S rats.
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-beta1 and -beta2, 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.
Medical College of Wisconsin, Department of Physiology, Milwaukee, Wisconsin 53226, USA.
Annette J
AJ
Dahly
Kimberly M
KM
Hoagland
Averia K
AK
Flasch
Sharda
S
Jha
Steven R
SR
Ledbetter
Richard J
RJ
Roman
D000758:Anesthesia; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001794:Blood Pressure; D024061:Collagen Type III / Q000235:genetics; D005353:Fibronectins / Q000235:genetics; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology / Q000628:therapy; D006977:Hypertension, Renal / Q000473:pathology / Q000628:therapy*; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D011507:Proteinuria / Q000628:therapy; D051381:Rats; D020303:Rats, Inbred Dahl; D012079:Renal Circulation; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2
D000911:Antibodies, Monoclonal; D024061:Collagen Type III; D005353:Fibronectins; D017673:Sodium Chloride, Dietary; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2