Angiotensin II blockade and low-protein diet produce additive therapeutic effects in experimental glomerulonephritis

Background. Transforming growth factor-beta (TGF-beta) overexpression plays a key role in the accumulation of extracellular matrix in acute and chroni c renal diseases. Recent studies have suggested that the degree of reductio n in pathological TGF-beta overexpression can be used as a therapeutic inde x to evaluate the antifibrotic potential of pharmacological angiotensin II (Ang II) blockade in renal disease. Using this target, we found that treatm ent with the angiotensin I-converting enzyme inhibitor enalapril or the Ang II type 1 receptor antagonist losartan reduced TGF-beta overexpression mor e effectively at doses dearly higher than those required to control blood p ressure. However, both forms of Ang II blockade were only partially effecti ve in normalizing TGF-beta expression. This study investigated whether a gr eater antifibrotic, TGF-beta-reducing benefit can be achieved when Ang II b lockade is combined with dietary protein restriction. Methods. Mesangioproliferative glomerulonephritis was induced in male Sprag ue-Dawley rats on a normal-protein diet. Treatment with a low-protein diet and/or maximally effective doses of enalapril or losartan was started one d ay after disease induction. On the fifth day, 24-hour urine protein excreti on was measured. On the sixth day, cortical kidney tissue was taken for per iodic acid-Schiff staining. Isolated glomeruli were used for mRNA extractio n or were placed in culture for determination of production of TGF-beta 1, the matrix protein fibronectin, and the protease inhibitor plasmin activato r inhibitor type 1 (PAI-1) by enzyme-linked immunosorbent assay. Results. Compared with untreated nephritic animals on a normal-protein diet , a single treatment with enalapril, losartan, or low-protein diet signific antly reduced glomerular TGF-beta production, albeit to a similar degree of approximately 45%. A moderate, but significant further reduction in pathol ogical TGF-beta expression of a total of 65% for enalapril and 60% for losa rtan was achieved when these drugs were combined with low-protein feeding. This reduction in TGF-beta overexpression paralleled decreased proteinuria, glomerular matrix accumulation, and overproduction of fibronectin and PAI- 1. Conclusions. Ang II blockade and low-protein diet have additive effects on disease reduction, suggesting that disease progression in humans with chron ic renal failure may be slowed more effectively when Ang II blockade and lo w-protein diet are combined. Since maximal pharmacological Ang II inhibitio n was used, it is likely that dietary protein restriction further reduces p athological TGF-beta overexpression by mechanisms different from those of e nalapril or losartan.