Antihypertensive effects of chronic anti-TGF-beta antibody therapy in Dahl S rats
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Annette J Dahly1, Kimberly M Hoagland, Averia K Flasch
1Medical College of Wisconsin, Department of Physiology, Milwaukee, Wisconsin 53226, USA.
Abstract:
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.
Insights
Transforming growth factor-beta (TGF-beta) antibody therapy lowered blood pressure and reduced kidney damage in salt-induced hypertension models. Early intervention with anti-TGF-beta Ab provided significant renoprotection, decreasing proteinuria and fibrosis.
Area of Science:
- Nephrology
- Cardiovascular Research
- Molecular Biology
Background:
- Hypertension and renal disease are significant health concerns.
- Transforming growth factor-beta (TGF-beta) plays a role in kidney disease development.
- Dahl salt-sensitive rats are a model for studying salt-induced hypertension.
Purpose of the Study:
- To investigate the role of TGF-beta in hypertension and renal disease.
- To evaluate the therapeutic potential of anti-TGF-beta antibody (anti-TGF-beta Ab) therapy.
- To assess the effects of early versus later intervention with anti-TGF-beta Ab.
Main Methods:
- Male Dahl salt-sensitive rats were fed a high-salt diet.
- Rats received intraperitoneal injections of control or anti-TGF-beta Ab.
- Blood pressure, proteinuria, renal blood flow, and renal injury markers were measured.
Main Results:
- Anti-TGF-beta Ab therapy significantly reduced mean arterial pressure and proteinuria.
- Medullary blood flow increased threefold in treated rats.
- Early intervention with anti-TGF-beta Ab reduced blood pressure, proteinuria, glomerulosclerosis, and medullary fibrosis.
Conclusions:
- Anti-TGF-beta Ab therapy is effective in reducing blood pressure and proteinuria in a rat model of hypertension.
- TGF-beta signaling is a viable therapeutic target for hypertension and associated renal injury.
- Early intervention with anti-TGF-beta Ab offers greater renoprotective benefits.
