Abstract
Progressive reduction in kidney function in patients following myocardial infarction (MI) is associated with an increase in circulating uremic toxins levels leading to increased extracellular matrix deposition. We have recently reported that treatment with uremic toxin adsorbent AST-120 in rats with MI inhibits serum levels of uremic toxin indoxyl sulfate (IS) and downregulates expression of cardiac profibrotic cytokine transforming growth factor beta (TGF-β1). In this study, we examined the effect of uremic toxins post-MI on cardiac microRNA-21 and microRNA-29b expression, and also the regulation of target genes and matrix remodeling proteins involved in TGFβ1 and angiotensin II signaling pathways. Sixteen weeks after MI, cardiac tissues were assessed for pathological and molecular changes. The percentage area of cardiac fibrosis was 4.67 ± 0.17 in vehicle-treated MI, 2.9 ± 0.26 in sham, and 3.32 ± 0.38 in AST-120-treated MI, group of rats. Compared to sham group, we found a twofold increase in the cardiac expression of microRNA-21 and 0.5-fold decrease in microRNA-29b in heart tissue from vehicle-treated MI. Treatment with AST-120 lowered serum IS levels and attenuated both, cardiac fibrosis and changes in expression of these microRNAs observed after MI. We also found increased mRNA expression of angiotensin-converting enzyme (ACE) and angiotensin receptor 1a (Agtr1a) in cardiac tissue collected from MI rats. Treatment with AST-120 attenuated both, expression of ACE and Agtr1a mRNA. Exposure of rat cardiac fibroblasts to IS upregulated angiotensin II signaling and altered the expression of both microRNA-21 and microRNA-29b. These results collectively suggest a clear role of IS in altering microRNA-21 and microRNA-29b in MI heart, via a mechanism involving angiotensin signaling pathway, which leads to cardiac fibrosis.
Highlights
Kidney dysfunction is a common consequence of myocardial infarction (MI), and results in a greater risk of inhospital death and cardiovascular events such as heart failure and stroke (Anavekar et al 2004; Goldberg et al 2005, 2009; Parikh et al 2008)
In AST-120-treated MI animals, the percentage of renal fibrosis was significantly attenuated compared to the vehicle MI group (P < 0.01) but was higher compared to sham animals (P < 0.001, Table 1)
angiotensin receptor 1a (Agtr1a) mRNA expression was 25% higher after 18 h of indoxyl sulfate (IS) treatment, this did not attain significance (Fig. 9B). Both Smad 3 and Smad 4 mRNA were significantly higher at 18 h after IS treatment (P < 0.05 for Smad 3 and P < 0.01 for Smad 4, Fig. 9C and D). This is the first study to report the regulation of cardiac microRNAs (21 and 29b) together with inhibition of fibrosis in the myocardium of MI rats after lowering uremic toxins levels
Summary
Kidney dysfunction is a common consequence of myocardial infarction (MI), and results in a greater risk of inhospital death and cardiovascular events such as heart failure and stroke (Anavekar et al 2004; Goldberg et al 2005, 2009; Parikh et al 2008). Indoxyl sulfate is a small nondialyzable protein-bound uremic toxin derived from dietary tryptophan. It is metabolized by the gut microflora to the precursor indole where it is absorbed across the gastrointestinal tract prior to its conjugation to IS by the liver (Lekawanvijit et al 2012b). Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
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