ANTIARRHYTHMIC EFFECT LINKED TO MELATONIN CARDIORENAL PROTECTION INVOLVES AT1 AND HSP70-VDR COUNTERBALANCE

NATALIA PRADO; MARIANA CASAROTTO; JUAN PABLO CALVO; LUCIANA MAZZEI; ISABEL MERCEDES GARCÍA; AMIRA PONCE ZUMINO; DARÍO CUELLO-CARRIÓN; MIGUEL FORNÉS; EMILIANO DIEZ; WALTER MANUCHA

JOURNAL OF PINEAL RESEARCH

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2018 vol. 65 p. 1 - 17

0742-3098

Lethal cardiovascular events -such as ventricular arrhythmias- are increased in patients with chronic kidney disease (CKD), and in this sense, there is a lack of specific treatments. Melatonin has been suggested as a protective factor linked to renin-angiotensin system counterbalance. Myocardial remodeling and arrhythmogenesis were related to low vitamin D receptor (VDR) expression linked to increased angiotensin II receptor type 1 (AT1) expression and oxidative stress. Melatonin increases the levels of heat shock protein 70 (Hsp70) -an antioxidant factor- as part of its protective effect. Therefore, this study attempted to determine whether an AT1-Hsp70-VDR counterbalance axis linked to melatonin could explain the prevention of kidney damage and heart remodeling. Unilateral ureteral-obstructed and sham-operated rats were treated with either melatonin (4 mg/kg/day) or vehicle for 15 days. In 5 hearts and kidneys from each group, we found that the obstructed rats showed a reduction in VDR/Hsp70 and an increase in AT1 and suffered oxidative stress, fibrosis, apoptosis, mitochondrial edema, and dilated crests. These changes were reversed by melatonin. Our results showed that the obstructed rats (8 additional hearts per group) had a higher incidence of ventricular fibrillation during reperfusion than did those that were treated with melatonin. The action potential duration was prolonged in melatonin-treated rats throughout the experiment. We conclude that melatonin prevents kidney damage and heart remodeling during unilateral ureteral obstruction due to a reduction in oxidative stress/fibrosis/apoptosis mediated by an AT1-Hsp70-VDR counterbalance axis. Unprecedentedly, decoupling of this axis may be related to myocardial remodelling and increased arrhythmogenesis, while melatonin can protect against these changes by counterbalance axis induction.