Cardiac calcium dysregulation in mice with chronic kidney disease.

Hung‐Yen Ke,Shih‐Ming Huang,Chih‐Yuan Lin,Yung‐Lung Chang,Chien‐Sung Tsai,Li‐Han Chin,Yen‐Hui Chen,Feng‐Zhi Lin,Yao‐Chang Chen

doi:10.1111/jcmm.15066

Abstract

Cardiovascular complications are leading causes of morbidity and mortality in patients with chronic kidney disease (CKD). CKD significantly affects cardiac calcium (Ca2+) regulation, but the underlying mechanisms are not clear. The present study investigated the modulation of Ca2+ 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 Ca2+ decay time, Ca2+ sparks, and Ca2+ leakage but lower [Ca2+]i transients and sarcoplasmic reticulum Ca2+ contents. The CaMKII inhibitor KN93 and ranolazine (RAN; late sodium current inhibitor) reversed the deterioration in Ca2+ 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 Ca2+ regulation and electrophysiological characteristics. These findings may apply on future clinical therapies.

Highlights

Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD).[1]
A recent study discovered that protein kinase A (PKA) phosphorylated PLB-Ser[16] and calmodulin-dependent protein kinase II (CaMKII) exclusively catalysed the phosphorylation of PLB-Thr17.25 Our study demonstrated increased phosphorylation of PLB-Thr[17] protein and no change in PLB-Ser[16] phosphorylation in CKD ventricles, which suggests higher CaMKII, not PKA, activity in CKD ventricles
These findings suggest that increased CaMKII in CKD ventricles was arrhythmogenic, and the increased sarcoplasmic reticulum (SR) Ca2+ leak was a crucial mechanism, which is consistent with our findings

Summary

| INTRODUCTION

Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD).[1]. One of the major pathological changes in cardiomyopathy is dysregulation of intracellular Ca2+ homeostasis, which is caused by functional alterations of the proteins involved in Ca2+ release and uptake across the sarcolemma and the sarcoplasmic reticulum (SR).[11] Decreased SR Ca2+ ATPase (SERCA) 2a activity was reported in experimental models of CKD in association with the prolongation of diastolic Ca2+ transients.[12,13] Cyclic adenosine monophosphate (cAMP) in human SR regulates the phosphorylation of phospholamban (PLB) via protein kinase A (PKA), which affects SERCA2 activity and Ca2+ transport. Inhalation of 3% isoflurane was performed to anaesthesia, until animals were sedated and maintained 1% isoflurane during the examination of echocardiography. First of all, it was to obtain 2D left ventricular (LV) short-axis images. Under isoflurane anaesthesia (5% for induction and 2% for maintenance), electrocardiograms (ECGs) were recorded from standard lead II limb leads via a bio-amplifier (ADInstruments), were connected to a ML845 Powerlab polygraph recorder (ADInstruments) and were continuously displayed throughout the experiment in sham or CKD mice

| MATERIALS AND METHODS

Findings

| DISCUSSION

| CONCLUSIONS