Heart Remodeling and Ischemia–Reperfusion Arrhythmias Linked to Myocardial Vitamin D Receptors Deficiency in Obstructive Nephropathy Are Reversed by Paricalcitol

Abstract

Cardiovascular disease is often associated with chronic kidney disease and vice versa; myocardial vitamin D receptors (VDRs) are among the probable links between the 2 disorders. The vitamin D receptor activator paricalcitol protects against some renal and cardiovascular complications. However, the structural and electrophysiological effects of myocardial vitamin D receptor modification and its impact on the response to ischemia-reperfusion are currently unknown. This work attempted to determine whether obstructive nephropathy induced myocardial changes (in rats) linked to vitamin D receptor deficiency and to ventricular arrhythmias in Langendorff-perfused hearts. Unilateral ureteral-obstructed and Sham-operated rats were treated with either paricalcitol (30 ng/kg/d intraperitoneal) or vehicle for 15 days. In 5 hearts from each group, we found that obstructed rats showed a reduction in VDRs and an increase in angiotensin II type 1 receptor expression (messenger RNA and protein), suffered fibrosis (determined by Masson trichrome stain) and myofibril reduction with an increase in mitochondrial size, and had dilated crests (determined by electron microscopy). These changes were reversed by paricalcitol. In 8 additional hearts per group, we found that obstructed rats showed a higher incidence of ventricular fibrillation during reperfusion (after 10 minutes of regional ischemia) than did those treated with paricalcitol. The action potential duration was prolonged throughout the experiment in paricalcitol-treated rats. We conclude that the reduction in myocardial vitamin D receptor expression in obstructed rats might be related to myocardial remodeling associated with an increase in arrhythmogenesis and that paricalcitol protects against these changes by restoring myocardial vitamin D receptor levels and prolonging action potentials.

Mediators and mechanisms of heat shock protein 70 based cytoprotection in obstructive nephropathy

“…These results thus show a novel strategy to prevent UUO-induced kidney damage by using chitosan/siRNA nanoparticles to knockdown COX-2 specifically in macrophages (Yang et al 2015). Moreover, mitochondrial abnormality has been shown in many kidney disease models Diez et al 2015;Manucha 2014;García et al 2014García et al , 2014. However, its role in the pathogenesis of CKD is still uncertain.…”

Role of Vitamin D in Cardiovascular Diseases

“…Further, reduced expression of myocardial vitamin D receptors in obstructive nephropathy rats is related to the myocardial remodeling with fibrosis with an increase in arrhythmogenesis. Protection against these changes by restoring myocardial vitamin D receptor levels with paricalcitol suggests the protective role of vitamin D [60]. …”

Antiarrhythmic effect linked to melatonin cardiorenal protection involves AT1 reduction and Hsp70‐VDR increase

“…Unprecedentedly, melatonin decreased renal and myocardial AT 1 overexpression. It is well documented that the AT 1 pathway leads to myocardial fibrosis during chronic kidney disease . As previously suggested, low AT 1 expression through vitamin D receptor induction could be a consequence of Hsp70‐mediated cell protection .…”

“…Myocardial/renal tissue samples from 5 hearts/kidneys from each group were fixed in 10% phosphate‐buffered formalin (pH = 7.1) for 24 to 48 hours before being embedded in paraffin and serially sectioned (5 μm) on a microtome (Leica). The paraffin sections were subjected to staining with Masson's trichrome stain, as previously described …”

“…Regarding the pathogenic mechanisms that relate cardiac and renal diseases, our laboratory has recently demonstrated that unilateral ureteral obstruction in rats is an adequate experimental model of chronic kidney disease that induces myocardial remodeling with increased arrhythmogenesis . This remodeling includes a reduction in myocardial vitamin D receptor expression linked to increased angiotensin II receptor type 1 expression, fibrosis, mitochondrial edema, and a higher incidence of reperfusion arrhythmias; and all of them could be related to oxidative stress.…”