Role of Indoxyl Sulfate as a Predisposing Factor for Atrial Fibrillation in Renal Dysfunction

Abstract

BackgroundRenal dysfunction is a major risk factor for atrial fibrillation (AF). The uremic toxin indoxyl sulfate may contribute to the progression of cardiac fibrosis and AF substrate in renal dysfunction.Methods and ResultsMale Sprague–Dawley rats were assigned randomly to the following groups: 5/6 nephrectomy (5/6Nx) with vehicle, 5/6Nx with AST‐120, sham procedure with vehicle, and sham procedure with AST‐120. Vehicle and AST‐120 were administered for 4 weeks. Serum levels of IS were significantly increased in 5/6Nx groups. Expression of malondialdehyde, an indicator of oxidative stress, was upregulated in the left atrium of 5/6Nx groups and was accompanied by an increase in expression of NADPH oxidase 2 and 4. Monocyte‐mediated inflammatory signals such as CD68, monocyte chemoattractant protein 1, and vascular cell adhesion molecule 1 were also upregulated in 5/6Nx groups. Interstitial fibrosis was promoted heterogeneously, and expression of profibrotic indicators such as transforming growth factor β1, α‐smooth muscle actin, and collagen type 1 was upregulated in left atrium tissue of 5/6Nx groups. In cultured atrial fibroblasts, incubation with IS upregulated expression of the markers of oxidative stress, inflammation, and profibrotic factors. These results suggest the direct effects of IS on the progression of AF substrate. AF was consistently and invariably induced by atrial extrastimuli in 5/6Nx groups in electrophysiological experiments. AST‐120 treatment significantly alleviated renal dysfunction–induced oxidative stress, inflammation, and atrial fibrosis and, consequently, attenuated AF inducibility.ConclusionsIndoxyl sulfate facilitates atrial fibrosis and AF and thus is a novel therapeutic target for prevention of renal dysfunction–induced AF.

Chronic kidney disease-induced atrial structural remodeling and atrial fibrillation: more studies on the pathological mechanism are encouraged

“…A study by Fukunaga et al successfully investigated the role of oxidative stress which mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the genesis of in the setting of 4 weeks post-5/6 nephrectomy rats, and demonstrated the antioxidant agent, sodium zinc dihydrolipoylhistidinate, is effective in reducing atrial oxidative stress, fibrosis, and AF inducibility (Fukunaga et al, 2012). In the similar animal setting, Aoki et al reported that renal dysfunction-induced uremic toxin indoxyl sulfate is also associated with increased oxidative stress, inflammation, profibrotic factors, and AF (Aoki et al, 2015). However, the role of TGF-β1/Smads pathway in CKD-induced AF is still not fully understood, and further research is needed.…”

Indoxyl Sulfate: A Novel Cardiovascular Risk Factor in Chronic Kidney Disease

“…By virtue of its proinflammatory and pro‐oxidant properties, indoxyl sulfate is implicated in the pathogenesis of at least 6 phenotypes of CVD in CKD (Figure ), including atherosclerosis, arteriosclerosis, congestive heart failure, arrhythmia, vascular access thrombosis, and peripheral arterial disease (PAD) …”

“…Indoxyl sulfate has been proven to induce arrhythmogenesis through oxidative stress in pulmonary veins, sinoatrial nodes, and left atria isolated from rabbit hearts . Recently, Aoki et al showed, in 5 of 6 nephrectomized rats, that indoxyl sulfate contributes to the increased inducibility of AF, which is significantly attenuated by AST‐120 treatment . Therefore, strategies for the prevention of AF will have to consider indoxyl sulfate as a novel risk factor for AF, in addition to other well‐established risk factors in CKD.…”

“…Inhibit endothelial proliferation and repair 26,27 Increase endothelial leukocyte adhesion 28,29 Promote cardiac fibrosis [34][35][36] Increase expression of tissue factor 40,41 Impair neovascularization mediated by EPC 42,43 Arteriosclerosis Increase VSMC proliferation 30,31 Increase vascular calcification 32,33 Increase arrhythmogenesis [37][38][39] activates mitogen-activated protein kinase in vitro. 30 Using human aortic smooth muscle cells (HASMCs), Muteliefu et al reported that indoxyl sulfate significantly promotes the proliferation of HASMCs, in a concentration-dependent manner, by inducing oxidative stress.…”

Indoxyl sulfate, a valuable biomarker in chronic kidney disease and dialysis

“…[30][31][32] Indoxyl sulfate facilitates atrial fibrillation. 33 It has been revealed that indoxyl sulfate stimulates vascular calcification via induction of oxidative stress and expression of osteoblast-specific proteins. 34 A recent research suggests that indoxyl sulfate may be related to impaired neovascularization and peripheral arterial disease in CKD.…”