Cardiac calcium dysregulation in mice with chronic kidney disease.

Cardiovascular complications are leading causes of morbidity and mortality in patients with chronic kidney disease (CKD). CKD significantly affects cardiac calcium (Ca(2+) ) regulation, but the underlying mechanisms are not clear. The present study investigated the modulation of Ca(2+) homeostasis in CKD mice. Echocardiography revealed impaired fractional shortening (FS) and stroke volume (SV) in CKD mice. Electrocardiography showed that CKD mice exhibited longer QT interval, corrected QT (QTc) prolongation, faster spontaneous activities, shorter action potential duration (APD) and increased ventricle arrhythmogenesis, and ranolazine (10 µmol/L) blocked these effects. Conventional microelectrodes and the Fluo-3 fluorometric ratio techniques indicated that CKD ventricular cardiomyocytes exhibited higher Ca(2+) decay time, Ca(2+) sparks, and Ca(2+) leakage but lower [Ca(2+) ](i) transients and sarcoplasmic reticulum Ca(2+) contents. The CaMKII inhibitor KN93 and ranolazine (RAN; late sodium current inhibitor) reversed the deterioration in Ca(2+) handling. Western blots revealed that CKD ventricles exhibited higher phosphorylated RyR2 and CaMKII and reduced phosphorylated SERCA2 and SERCA2 and the ratio of PLB-Thr17 to PLB. In conclusions, the modulation of CaMKII, PLB and late Na(+) current in CKD significantly altered cardiac Ca(2+) regulation and electrophysiological characteristics. These findings may apply on future clinical therapies.