TARGETING TGF-BETA OVEREXPRESSION IN RENAL-DISEASE - MAXIMIZING THE ANTIFIBROTIC ACTION OF ANGIOTENSIN-II BLOCKADE

Background. Overproduction of transforming growth factor-beta (TGF-bet a) is a key mediator of extracellular matrix accumulation in fibrotic diseases. We hypothesized that the degree of reduction of pathological TGF-beta expression can be used as a novel index of the antifibrotic potential of angiotensin II (Ang II) blockade in renal disease. Method s. One day after induction of Thy 1.1 glomerulonephritis, rats were tr eated with increasing doses of the Ang I converting enzyme (ACE) inhib itor enalapril and/or the Ang II receptor blocker losartan in the drin king water. Six days after disease induction the therapeutic effect on glomerular TGF-beta overexpression was evaluated. Results. Both enala pril and losartan reduced TGF-beta overproduction in a dose-dependent manner, showing a moderate reduction at doses known to control blood p ressure in renal forms of hypertension. A maximal reduction in TGF-bet a expression of approximately 45% was seen for both drugs starting at 100 mg/liter enalapril and 500 mg/liter losartan, with no further redu ction at doses of enalapril up to 1000 mg/liter or losartan up to 2500 mg/liter. Go-treatment with both drugs was not superior to single the rapy. Consistent with our hypothesis that reduction in TGF-P expressio n is a valid target, other disease measures, including glomerular matr ix accumulation, glomerular production and mRNA expression of the matr ix protein fibronectin and the protease inhibitor plasminogen-activato r-inhibitor type 1 (PAI-1) closely followed TGF-beta expression. Concl usions. 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 m echanisms.