Document Detail

Angiotensin II blockade and low-protein diet produce additive therapeutic effects in experimental glomerulonephritis.
MedLine Citation:
PMID:  10760085     Owner:  NLM     Status:  MEDLINE    
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.
H Peters; W A Border; N A Noble
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Kidney international     Volume:  57     ISSN:  0085-2538     ISO Abbreviation:  Kidney Int.     Publication Date:  2000 Apr 
Date Detail:
Created Date:  2000-05-09     Completed Date:  2000-05-09     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0323470     Medline TA:  Kidney Int     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1493-501     Citation Subset:  IM    
Fibrosis Research Laboratory, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
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MeSH Terms
Angiotensin II / antagonists & inhibitors*
Angiotensin-Converting Enzyme Inhibitors / therapeutic use
Diet, Protein-Restricted*
Enalapril / therapeutic use
Glomerulonephritis / therapy*
Losartan / therapeutic use
Rats, Sprague-Dawley
Receptor, Angiotensin, Type 1
Receptor, Angiotensin, Type 2
Receptors, Angiotensin / antagonists & inhibitors
Transforming Growth Factor beta / antagonists & inhibitors
Treatment Outcome
Grant Support
Reg. No./Substance:
0/Angiotensin-Converting Enzyme Inhibitors; 0/Receptor, Angiotensin, Type 1; 0/Receptor, Angiotensin, Type 2; 0/Receptors, Angiotensin; 0/Transforming Growth Factor beta; 11128-99-7/Angiotensin II; 114798-26-4/Losartan; 75847-73-3/Enalapril

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