LAUSR

2695-Pos Board B302 The Uremic Toxin P-Cresol Reduces Cell Surface Expression of Human Ether-A-Go Go-Related Gene (hERG) Channels via the Ubiquitin Ligase Nedd4-2 Ellen G. Avery, Shawn Lamothe, Shetuan Zhang, Jun Guo, Wentao Li, Tonghua Yang. Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada. 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 the hERG current can cause long QT syndrome, leading to potentially fatal cardiac arrhythmias. In chronic kidney disease (CKD), the risk of sudden death is increased beyond what is explicable by traditional risk factors for cardiovascular disease. The molecular mechanisms governing CKD-induced cardiac arrhythmia are unknown, but a significant portion of CKD patients have prolonged QT interval. In CKD, a large number of compounds, which under normal conditions are excreted by kidney, are progressively accumulated. These compounds are known as uremic toxins, and are known to negatively affect the biological functions. Serum concentrations of the uremic toxin p-cresol increase up to 30-fold in CKD patients compared to normal population. Increased serum p-cresol level has been associated with QT interval prolongation in patients with end stage renal failure, though a causative link has not been established. Impairment of hERG function is a common cause of long QT syndrome, so we investigated the effects of p-cresol on hERG channels using whole-cell voltage clamp and Western blot analysis. We found that p-cresol selectively decreased the mature hERG protein expression and the hERG current. However, p-cresol had no effect on the Nedd4-2 interaction-deficient mutant hERG channels. These data suggest that Nedd4-2 may be involved in p-cresol mediated hERG reduction. In isolated rat neonatal ventricular myocytes, p-cresol decreased IKr and prolonged action potential duration. These results suggest that p-cresol-mediated hERG reduction may contribute to the prolonged QT in CKD patients.