Indoxyl sulfate reduces Ito,f by activating ROS/MAPK and NF-κB signaling pathways

Abstract

There is a high prevalence of ventricular arrhythmias related to sudden cardiac death in patients with chronic kidney disease (CKD). To explored the possible mechanism of CKD-related ventricular arrhythmias, a CKD rat model was created, and indoxyl sulfate (IS) was further used in vivo and in vitro. This project used the following methods: patch clamp, electrocardiogram, and some molecular biology experimental techniques. IS was found to be significantly elevated in the serum of CKD rats. Interestingly, the expression levels of the fast transient outward potassium current–related (I to,f -related) proteins (Kv4.2, Kv4.3, and KChIP2) in the heart of CKD rats and rats treated with IS decreased. IS dose-dependently reduced I to,f density, accompanied by the decreases in Kv4.2, Kv4.3, and KChIP2 proteins in vitro. IS also prolonged the action potential duration and QT interval, and paroxysmal ventricular tachycardia could be induced by IS. In-depth studies have shown that ROS/p38MAPK, ROS–p44/42 MAPK, and NF-κB signaling pathways play key roles in the reduction of I to,f density and I to,f -related proteins caused by IS. These data suggest that IS reduces I to,f -related proteins and I to,f density by activating ROS/MAPK and NF-κB signaling pathways, and the action potential duration and QT interval are subsequently prolonged, which contributes to increasing the susceptibility to arrhythmia in CKD.

Metabolic Homeostasis of Amino Acids and Diabetic Kidney Disease

“…As a typical aryl hydrocarbon receptor (AHR) ligand, IS activates AHR and then induces endothelial dysfunction, endoplasmic reticulum (ER) stress, podocyte injury, interstitial fibrosis, and glomerular damage in experimental animal models of metabolic syndrome [ 36 ]. In progression of renal-function decline in CKD mammal models, IS not only stimulates nuclear translocation of phosphorylated NF-κB p65 to induce activation of NF-κB signaling [ 37 ] but also aggravates renal fibrosis via upregulation of TGF-β1, plasminogen activator inhibitor-1 (PAI-1), the tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), and pro-α1 (I) collagen [ 38 , 39 ] ( Figure 2 ). Due to IS production dependence on indole-producing bacteria ( Bacteroides spp.…”

Chronic Kidney Disease: A Nerve-Racking Situation for the Heart

“…11 In conclusion, the study by Hohl, Selejan, Wintrich, and their colleagues supports the notion that chronic sympathetic overactivity in CKD promotes dysfunction in other organs, and provides a novel dimension in considering pathophysiology of multiorgan dysfunction. Notably kidney disease also represents a state where uremic toxins are likely to increase the proclivity to adverse electrophysiological effects on cardiac myocytes 12 ; however, the current study explores a novel angle and implicates sympathetic hyperactivity. The work also highlights the need for continued investigations based on the principles of integrative physiology in health and disease.…”

Cardiovascular Consequences of Uremic Metabolites: an Overview of the Involved Signaling Pathways

“…73 Therefore, IS reduces mRNA levels of voltage-gated α pore-forming subunits Kv4.2 and Kv4.3 and the accessory β subunit KChIP2. 73 IS also modulates Cx43-composed gap junctions essential in cardiomyocyte synchronization 74 by downregulating Cx43 mRNA levels and reducing Cx43 protein levels. 74 IS-mediated oxidative stress induces vascular disease, resulting in coronary atherosclerosis and vascular calcification.…”

“…72 Furthermore, NOX-2-mediated ROS production with its downstream phosphorylation of NFkB, p38-MAPK, and p42/44-MAPK induces consequent reduction of fast transient outward potassium current density and fast transient outward potassium current-related proteins, with effects on the early repolarization period and the duration of the AP. 73 Therefore, IS reduces mRNA levels of voltage-gated α pore-forming subunits Kv4.2 and Kv4.3 and the accessory β subunit KChIP2. 73 IS also modulates Cx43-composed gap junctions essential in cardiomyocyte synchronization 74 by downregulating Cx43 mRNA levels and reducing Cx43 protein levels.…”