SP042MATERNAL MELATONIN OR AGOMELATINE THERAPY REPROGRAMS THE DEVELOPMENT OF HYPERTENSION IN MALE RATS BORN BY MOTHER EXPOSED TO CONTINUOUS LIGHT

Abstract

INTRODUCTION AND AIMS: Environmental disturbance of the circadian rhythm is associated with the development of hypertension. Hypertension can originate from early-life insults. Adult rats exposed to continuous light cause melatonin deficiency and leads to hypertension, while it is unclear whether maternal continuous light exposure can induce programmed hypertension in adult offspring. We reported previously that melatonin can be protective in a variety of models of programmed hypertension. Therefore, the present study examined whether maternal melatonin or its analogue agomelatine therapy prevented maternal continuous light exposure-induced programmed hypertension in adult offspring and explored the melatonin signaling pathway in the kidneys. Additionally, we employed the whole-genome RNA nextgeneration sequencing (NGS) to further quantify the abundance of RNA transcripts in the offspring kidney from maternal exposure to continuous light, melatonin, or agomelatine. METHODS: Female Sprague-Dawley pregnant rats randomly divided into four groups: controls, rats exposed to continuous light, exposed to continuous light plus treated with agomelatine (50mg/day i.p.), and exposed to continuous light plus treated with 0.01 % melatonin in drinking water throughout pregnancy and lactation period. Male offspring (n=10/group) were sacrificed at 12 weeks of age. RESULTS: Maternal continuous light exposure induced hypertension in male offspring, which was prevented by melatonin or agomelatine therapy. Maternal exposure to continuous light impaired melatonin synthesis and signaling in the developing kidney, but not persisted into adulthood. Continuous light exposure modified 718 renal transcripts in developing offspring kidney analyzed by RNA next generation sequencing (NGS). Our NGS data showed peroxisome proliferatoractivated receptor (PPAR) signaling pathway is significantly regulated pathway among different groups. Genes that belong to the renin-angiotensin system (RAS), sodium transporters, AMP-activated protein kinase (AMPK) pathway, and circadian rhythm were potentially involved in the maternal exposure to continuous light-induced programmed hypertension. Maternal agomelatine therapy decreased Ace expression but increased Agtr2 and Mas1. Maternal melatonin therapy prevented the increases of Slc9a3, Slc12a3, and Atp1a1 expression induced by maternal continuous light exposure. CONCLUSIONS: Maternal melatonin or agomelatine therapy prevents programmed hypertension induced by maternal exposure to continuous light. Agomelatine and melatonin reprogram the RAS and sodium transporters differentially, to prevent programmed hypertension. By providing new information of candidate pathways on BP regulation whose effects can be modified by agomelatine or melatonin, our NGS results are of significance to the development of novel interventions in the prevention of programmed hypertension in children exposed to maternal night shift work and circadian disruption.