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 chronic renal diseases. Recent studies have suggested that the degree of reduction in pathological TGF-beta overexpression can be used as a therapeutic index to evaluate the antifibrotic potential of pharmacological angiotensin II (Ang II) blockade in renal disease. Using this target, we found that treatment with the angiotensin I-converting enzyme inhibitor enalapril or the Ang II type 1 receptor antagonist losartan reduced TGF-beta overexpression more effectively at doses clearly higher than those required to control blood pressure. However, both forms of Ang II blockade were only partially effective in normalizing TGF-beta expression. This study investigated whether a greater antifibrotic, TGF-beta-reducing benefit can be achieved when Ang II blockade is combined with dietary protein restriction.


METHODS
Mesangioproliferative glomerulonephritis was induced in male Sprague-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 day after disease induction. On the fifth day, 24-hour urine protein excretion was measured. On the sixth day, cortical kidney tissue was taken for periodic acid-Schiff staining. Isolated glomeruli were used for mRNA extraction or were placed in culture for determination of production of TGF-beta1, the matrix protein fibronectin, and the protease inhibitor plasmin activator 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 significantly reduced glomerular TGF-beta production, albeit to a similar degree of approximately 45%. A moderate, but significant further reduction in pathological TGF-beta expression of a total of 65% for enalapril and 60% for losartan 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 chronic renal failure may be slowed more effectively when Ang II blockade and low-protein diet are combined. Since maximal pharmacological Ang II inhibition was used, it is likely that dietary protein restriction further reduces pathological TGF-beta overexpression by mechanisms different from those of enalapril or losartan.
Peters
H
H
Fibrosis Research Laboratory, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
Border
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WA
Noble
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D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D018753:Diet, Protein-Restricted; D004656:Enalapril / Q000627:therapeutic use; D005921:Glomerulonephritis / Q000628:therapy*; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D004656:Enalapril; D019808:Losartan