Disruption of hERG Channel Function by the Uremic Toxin p-Cresol

Abstract

The human ether-a-go-go-related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (IKr), which is critical for cardiac repolarization. A reduction in hERG current can cause long QT syndrome (LQTS), leading to potentially fatal cardiac arrhythmias. In Chronic Kidney Disease (CKD), the risk of sudden cardiac death (SCD) is increased beyond what is explicable by traditional risk factors for cardiovascular disease. The molecular mechanisms governing CKD-induced cardiac arrhythmias are unknown, but a significant portion of CKD patients have prolonged QT intervals. In CKD, a large number of compounds, which would normally be excreted by the kidneys, are progressively accumulated. These compounds are known as uremic toxins and have been shown to negatively affect a variety of biological functions. Serum concentrations of the uremic toxin p-Cresol (pC) increase exponentially in CKD patients. Increased pC has been correlated with QT interval prolongation in patients, but no causative link has been established. Impairment of hERG function is a common cause of LQTS, so we investigated the effects of pC on hERG protein expression and current. We found that pC chronically reduces both hERG current and protein expression at the plasma membrane. Our findings suggest that pC acts through a Nedd4-2 dependent mechanism to decrease hERG. Our results from stable hERG-HEK cells are corroborated with data collected from cultured neonatal rat ventricular myocytes. We also demonstrate in an in vivo rabbit model that pC injection results in a prolongation of the QT interval. The results presented in this study suggest that pC may play a role in CKD-related LQTS.