Cardiac calcium dysregulation in mice with chronic kidney disease

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.

A systematic review and meta-analysis of murine models of uremic cardiomyopathy

“…Only 3 studies performed a cardiac analysis in long experimental setups beyond 12 weeks. 17,25,45 Cardiac hypertrophy and diastolic dysfunction were reported 14 weeks after SNX, 25 although cardiac fibrosis could not be detected 16 weeks postsurgery. 17 At 24 weeks postsurgery, systolic dysfunction was reported, though without altered left ventricular dimensions or induction of cardiac hypertrophy.…”

“…17 At 24 weeks postsurgery, systolic dysfunction was reported, though without altered left ventricular dimensions or induction of cardiac hypertrophy. 45 Further bilateral kidney surgery models. Bilateral ischemia/ reperfusion injury induced cardiac hypertrophy and fibrosis after 4 to 8 weeks, though without effect on systolic function.…”

“…In addition to the cardiac pathophysiological changes (inflammation, hypertrophy, and fibrosis) as well as findings on left ventricular morphology and function presented in b a s i c r e s e a r c h Supplementary Tables S3-S6, CKD-induced alterations in cardiomyocyte cellular function may affect cardiovascular risk, such as for intracellular calcium handling and cardiomyocyte shortening as readouts of cellular contraction. For example, cardiomyocytes from C57BL/6 mice subjected to SNX for 6 to 24 weeks displayed impaired systolic intracellular Ca 2þ dynamics 27,33,36,45 and reduced cell shortening as well as proarrhythmogenic diastolic Ca 2þ leaks. 27,36,45 Increased cardiac expression of the atrial and brain natriuretic peptides is also frequently used as a biomarker of cardiac damage and/or hypertrophy.…”

“…For example, cardiomyocytes from C57BL/6 mice subjected to SNX for 6 to 24 weeks displayed impaired systolic intracellular Ca 2þ dynamics 27,33,36,45 and reduced cell shortening as well as proarrhythmogenic diastolic Ca 2þ leaks. 27,36,45 Increased cardiac expression of the atrial and brain natriuretic peptides is also frequently used as a biomarker of cardiac damage and/or hypertrophy. Expression of atrial and brain natriuretic peptide was often reported to be increased in animal models of CKD; however, it did not always correlate with effects on heart weight or cardiomyocyte size as most frequently used parameters of cardiac hypertrophy (Supplementary Table S8), with a similar finding previously observed in a systematic review of animal models of diabetic cardiomyopathy.…”

An Overview of the Role of Calcium/Calmodulin-Dependent Protein Kinase in Cardiorenal Syndrome

“…In addition, incidence of CVDs have been increasing alongside incidence of CKDs worldwide (Thomas et al, 2017), showing the importance of studies regarding CRS type 4, for example. Besides, CKDs significantly affects the regulation of cardiac Ca 2+ by mechanisms not yet clarified (Ke et al, 2020).…”