RESUMO
BACKGROUND: Although a role of platelets is well established in atherosclerosis, only little is known about their contribution to pathologic renal matrix expansion. The present study analyzes the effect of the platelet inhibitor clopidogrel on the early injury and subsequent repair phase of experimental anti-thy1 glomerulonephritis. METHODS: In male Sprague-Dawley rats, acute anti-thy1 glomerulonephritis was induced by intravenous injection of OX-7 antibody. In protocol 1 (injury), clopidogrel was given starting 5 days before antibody injection. One day after disease induction, parameters of mesangial cell injury (glomerular cell number, inducible NO synthesis, and macrophage infiltration) were analyzed. In protocol 2 (repair), clopidogrel treatment was started one day after antibody injection. On day 6, parameters of glomerular repair [glomerular matrix score, expression of transforming growth factor (TGF)-beta 1, fibronectin, and plasminogen activator inhibitor (PAI)-1] and thrombosis (aneurysm formation and fibrinogen deposition) were determined. In both protocols, an additional group of rats was treated with the angiotensin-converting enzyme (ACE) inhibitor enalapril. RESULTS: In the injury protocol, platelet inhibition did not affect mesangial cell lysis, glomerular NO production, and macrophage infiltration, while ACE inhibition was protective. In the repair protocol, clopidogrel significantly limited aneurysm formation and fibrinogen deposition, as well as glomerular matrix expansion, TGF-beta 1, fibronectin, and PAI-1 expression. In comparison, enalapril was less effective in preventing glomerular thrombosis, but was significantly superior to clopidogrel in limiting matrix protein expression and accumulation. CONCLUSION: The present study shows that platelets play a significant role in the sequence from mesangial cell injury to renal matrix expansion in anti-thy1 glomerulonephritis. The results, directly comparing renin-angiotensin-system and platelet inhibition, suggest that platelets contribute less than angiotensin II to TGF-beta overexpression and matrix accumulation in this model of acute glomerular wound repair.
