Abstract 11416: Reduction of Renal Fibrosis as Well as Cardiac Pro-fibrotic and Pro-Inflammatory mRNA Expression by an Oral Charcoal Adsorbent, AST-120, in Post-MI Rats
Introduction: Pathological renal interstitial fibrosis occurs following myocardial infarction (MI) in the rat. Indoxyl sulfate (IS), a uremic toxin, is increased in chronic kidney disease (CKD), and appears to be contributory to both renal and cardiac fibrosis. Reducing IS by the gut adsorbent AST-120 has recently been demonstrated by us to reduce cardiac fibrosis in a CKD model. This study aimed to determine whether AST-120 has beneficial effects on renal and cardiac fibrosis post-MI.
Methods: MI-induced Sprague-Dawley rats were randomized to receive either AST-120 (dose 8% in rat chow) (n=14) or were untreated (n=9) for 16 weeks. Sham operated rats (n=8) served as controls. Serum IS level was measured at baseline and 16 weeks. Echocardiography and glomerular filtration rate (GFR/kg) was assessed prior to sacrifice at 16 weeks. Tissues were assessed for pathological changes using histological methods, western blot analysis and real-time PCR.
Results: Compared to sham, MI+Veh animals had reduced GFR/kg (p<0.05), a 2.2-fold increase in serum IS levels (p<0.05) and increased heart weight (p<0.01). Ejection fraction and fractional shortening was reduced by 42% and 51% respectively (P<0.0001) in MI+Veh animals, and the diastolic parameter isovolumetric relaxation time was increased by 27% (P<0.05). Treatment with AST-120 did not significantly attenuate these cardiac changes. MI animals showed an increase in renal interstitial fibrosis (p<0.0001) and cardiac fibrosis in non-infarct myocardium (p<0.01) as well as increased cardiac TGF-β1 (p<0.01) and TNF-α (p<0.05) mRNA expression. Serum IS was reduced with AST-120 (p<0.001), associated with reduced renal interstitial fibrosis vs untreated MI (p<0.05). There was no difference in infarct size between MI groups. Despite no overall change in cardiac function and fibrosis, TGF-β and TNF-α mRNA expression in the non-infarct zone was decreased by AST-120 vs untreated MI (p<0.05).
Conclusions: Treatment with AST-120 post-MI reduces renal interstitial fibrosis and normalizes cardiac TGF-β and TNF-α gene expression in association with reduced IS levels. Reduction of IS by AST-120 has beneficial effects post-MI, suggesting a potential clinical role in this setting.
- © 2011 by American Heart Association, Inc.