Impact of Melatonin in Programmed Hypertension and Kidney Disease: Interrelationship among Oxidative Stress, Epigenetic Regulation, and Circadian Clock

Hypertension and chronic kidney disease (CKD) are highly prevalent diseases globally. Suboptimal conditions in pregnancy can elicit long-term effects on the health of offspring a process referred to as “developmental programming”. The developing kidney is particularly susceptible to the insults of programming. We recently observed that programmed hypertension developed in the male offspring of rats exposed a variety of insults including maternal caloric restriction, diabetes, and nitric oxide (NO) inhibition. We also observed that melatonin prevents programmed hypertension in a variety of programming models. Although several mechanisms, like oxidative stress and epigenetic regulation, have been proposed to interpret programmed hypertension, the protective effects of melatonin on renal transcriptome to prevent programmed hypertension and kidney disease remain unclear. Melatonin is an endogenously produced indoleamine. Melatonin has several important physiological functions, including resetting of circardian clock, epigenetic regulation, and antioxidants. Given that melatonin can modulate oxidative stress and epigenetic and that blood pressure control is dependent on circadian clock, we therefore hypothesize that three important mechanisms are involved in the protective role of melatonin on programmed hypertension and kidney disease—Oxidative stress, epigenetic regulation, and circadian clock. Thereby we intend to use 3 different models with various insults to examine mechanistic pathways causing programming processes in this study: (1) maternal NG-nitro-L-arginine-methyester (L-NAME) exposure model, (2) continuous light exposure model, and (3) maternal high methyl-donor diet (or methyl-deficient diet) model. First, our recent report demonstrated that NO inhibition by L-NAME during pregnancy induced hypertension in male offspring at 12 weeks of age. Second, chronic continuous light exposure leads to melatonin deficiency resulting in hypertension development in rats. Third, high methyl-donor diet (or methyl deficiency diet) was reported to alter components of the DNA methylation machinery during organogenesis. We also intend to test whether N-acetylcysteine (NAC, a precursor of glutathione), melatonin receptor agonist, and DNA methyltransferase (DNMT) inhibitor can be therapeutic approaches to prevent the development of hypertension and kidney disease in these 3 models. The proposed studies in this 3-year project address the following three specific aims: 1) To prove maternal L-NAME treatment, continuous light exposure, and high methyl-donor diet induce developmental programming of adult kidney disease and hypertension in male adult offspring. 2) To investigate whether oxidative stress, epigenetic regulation, and circadian clock are major mechanisms cause programmed hypertension and kidney disease in these models. 3) To prevent the development of hypertension and kidney disease by melatonin, NAC, melatonin receptor agonist, and DNMT inhibitor. Toward a better understanding of protective role of melatonin on developmental programming will enable ideal care to reduce the future economic burden of CKD and hypertension in Taiwan.

Project ID:PC10601-0433
External Project ID:MOST104-2314-B182-056-MY3