Elsevier

Kidney International

Volume 54, Issue 5, November 1998, Pages 1570-1580
Kidney International

Cell Biology – Immunology – Pathology
Targeting TGF-β overexpression in renal disease: Maximizing the antifibrotic action of angiotensin II blockade

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Targeting TGF-β overexpression in renal disease: Maximizing the antifibrotic action of angiotensin II blockade

Background

Overproduction of transforming growth factor-β (TGF-β) is a key mediator of extracellular matrix accumulation in fibrotic diseases. We hypothesized that the degree of reduction of pathological TGF-β expression can be used as a novel index of the antifibrotic potential of angiotensin II (Ang II) blockade in renal disease.

Methods

One day after induction of Thy 1.1 glomerulonephritis, rats were treated with increasing doses of the Ang I converting enzyme (ACE) inhibitor enalapril and/or the Ang II receptor blocker losartan in the drinking water. Six days after disease induction the therapeutic effect on glomerular TGF-β overexpression was evaluated.

Results

Both enalapril and losartan reduced TGF-β overproduction in a dose-dependent manner, showing a moderate reduction at doses known to control blood pressure in renal forms of hypertension. A maximal reduction in TGF-β expression of approximately 45% was seen for both drugs starting at 100 mg/liter enalapril and 500 mg/liter losartan, with no further reduction at doses of enalapril up to 1000 mg/liter or losartan up to 2500 mg/liter. Co-treatment with both drugs was not superior to single therapy. Consistent with our hypothesis that reduction in TGF-β expression is a valid target, other disease measures, including glomerular matrix accumulation, glomerular production and mRNA expression of the matrix protein fibronectin and the protease inhibitor plasminogen-activator-inhibitor type 1 (PAI-1) closely followed TGF-β expression.

Conclusions

The data suggest that these therapies act through very similar pathways and that, in order to more effectively treat renal fibrosis, these drugs must be combined with other drugs that act by different mechanisms.

Keywords

transforming growth factor-β
enalapril
losartan
fibrosis
glomerulonephritis

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