Open AccessCardiac calcium dysregulation in mice with chronic kidney disease
Author(s) -
Ke HungYen,
Chin LiHan,
Tsai ChienSung,
Lin FengZhi,
Chen YenHui,
Chang YungLung,
Huang ShihMing,
Chen YaoChang,
Lin ChihYuan
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.15066
Subject(s) - ranolazine , medicine , ventricle , kidney disease , endocrinology , ryanodine receptor 2 , cardiology , calcium , homeostasis , afterdepolarization , ryanodine receptor , electrophysiology , repolarization
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.