The mechanisms underlying
chronic kidney disease (CKD)-associated higher risks for life-threatening
ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral
nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or
sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood
urea nitrogen and
creatinine levels and a longer electrocardiographic QTc interval than did the
sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to
sham EPI cardiomyocytes. A significant reduction of the transient outward
potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Ito currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4
protein expression. Incubation of plasma
electronegative low-density lipoprotein (
LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2
proteins in the EPI region, which may promote susceptibility to
ventricular tachyarrhythmias. Electronegative
LDL may underlie downregulation of KChIP2 in CKD.