Melatonin is a hormone produced by the pineal gland, predominantly at night, and plays a pivotal role in regulating the circadian rhythm as well as a variety of biological functions, including anti-inflammation, anti-oxidation, inhibition of sympathetic nerve activity, and preservation of endothelial cell function. The intrarenal renin–angiotensin system (RAS) is one of the most important contributors in the pathophysiology of chronic kidney disease (CKD) and hypertension, independent of the circulating RAS, due to sodium reabsorption and inflammation and fibrosis in the kidney. However, the relationship between melatonin secretion and intrarenal RAS activation has remained unknown. It has been recently shown that impaired nighttime melatonin secretion is associated with nighttime urinary angiotensinogen excretion, a surrogate marker of intrarenal RAS activation and renal damage in patients with CKD. Moreover, it has also been indicated that melatonin administered exogenously exercises antioxidant effects that ameliorate intrarenal RAS activation and renal injury in chronic progressive CKD animal models. As a result, the new roles of melatonin in suppressing RAS in the kidney via amelioration of reactive oxygen species have been clarified. Therefore, we review the relationship between melatonin and intrarenal RAS activation and indicate the possibility of a new strategy to suppress CKD, which is a risk factor for cardiovascular and end-stage renal diseases.
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Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336:186–95.
Russcher M, Koch B, Nagtegaal E, van der Putten K, ter Wee P, Gaillard C. The role of melatonin treatment in chronic kidney disease. Front Biosci. 2012;17:2644–56.
Grossman E, Laudon M, Zisapel N. Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials. Vasc Health Risk Manag. 2011;7:577–84.
Koch BC, van der Putten K, Van Someren EJ, Wielders JP, Ter Wee PM, Nagtegaal JE, et al. Impairment of endogenous melatonin rhythm is related to the degree of chronic kidney disease (CREAM study). Nephrol Dial Transplant. 2010;25:513–9.
Quiroz Y, Ferrebuz A, Romero F, Vaziri ND, Rodriguez-Iturbe B. Melatonin ameliorates oxidative stress, inflammation, proteinuria, and progression of renal damage in renal mass reduction. Am J Physiol Ren Physiol. 2008;294:F336–44.
Escribano BM, Moreno A, Tasset I, Tunez I. Impact of light/dark cycle patterns on oxidative stress in an adriamycin-induced nephropathy model in rats. PLoS ONE. 2014;9:e97713.
Agabiti-Rosei C, Favero G, De Ciuceis C, Rossini C, Porteri E, Rodella LF, et al. Effect of long-term treatment with melatonin on vascular markers of oxidative stress/inflammation and on the anticontractile activity of perivascular fat in aging mice. Hypertens Res. 2017;40:41–50.
Kobori H, Nangaku M, Navar LG, Nishiyama A. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev. 2007;59:251–87.
Navar LG, Harrison-Bernard LM, Nishiyama A, Kobori H. Regulation of intrarenal angiotensin II in hypertension. Hypertension. 2002;39:316–22.
Kobori H, Katsurada A, Ozawa Y, Satou R, Miyata K, Hase N, et al. Enhanced intrarenal oxidative stress and angiotensinogen in IgA nephropathy patients. Biochem Biophys Res Commun. 2007;22:156–63.
Yamamoto T, Nakagawa T, Suzuki H, Ohashi N, Fukasawa H, Fujigaki Y, et al. Urinary angiotensinogen as a marker of intrarenal angiotensin II activity associated with deterioration of renal function in patients with chronic kidney disease. J Am Soc Nephrol. 2007;18:1558–65.
Kobori H, Ohashi N, Katsurada A, Miyata K, Satou R, Saito T, et al. Urinary angiotensinogen as a potential biomarker of severity of chronic kidney diseases. J Am Soc Hypertens. 2008;2:349–54.
Kobori H, Alper AB Jr, Shenava R, Katsurada A, Saito T, Ohashi N, et al. Urinary angiotensinogen as a novel biomarker of the intrarenal renin-angiotensin system status in hypertensive patients. Hypertension. 2009;53:344–50.
Saito T, Urushihara M, Kotani Y, Kagami S, Kobori H. Increased urinary angiotensinogen is precedent to increased urinary albumin in patients with type 1 diabetes. Am J Med Sci. 2009;338:478–80.
Nishiyama A, Konishi Y, Ohashi N, Morikawa T, Urushihara M, Maeda I, et al. Urinary angiotensinogen reflects the activity of intrarenal renin-angiotensin system in patients with IgA nephropathy. Nephrol Dial Transplant. 2011;26:170–7.
Kobori H, Nishiyama A, Abe Y, Navar LG. Enhancement of intrarenal angiotensinogen in Dahl salt-sensitive rats on high salt diet. Hypertension. 2003;41:592–7.
Kobori H, Prieto-Carrasquero MC, Ozawa Y, Navar LG. AT1 receptor mediated augmentation of intrarenal angiotensinogen in angiotensin II-dependent hypertension. Hypertension. 2004;43:1126–32.
Kobori H, Ozawa Y, Suzaki Y, Nishiyama A. Enhanced intrarenal angiotensinogen contributes to early renal injury in spontaneously hypertensive rats. J Am Soc Nephrol. 2005;16:2073–80.
Miyata K, Ohashi N, Suzaki Y, Katsurada A, Kobori H. Sequential activation of the reactive oxygen species/angiotensinogen/renin-angiotensin system axis in renal injury of type 2 diabetic rats. Clin Exp Pharmacol Physiol. 2008;35:922–7.
Ohashi N, Katsurada A, Miyata K, Satou R, Saito T, Urushihara M, et al. Role of activated intrarenal reactive oxygen species and renin-angiotensin system in IgA nephropathy model mice. Clin Exp Pharmacol Physiol. 2009;36:750–5.
Urushihara M, Ohashi N, Miyata K, Satou R, Acres OW, Kobori H. Addition of angiotensin II type 1 receptor blocker to CCR2 antagonist markedly attenuates crescentic glomerulonephritis. Hypertension. 2011;57:586–93.
Ohashi N, Yamamoto T, Huang Y, Misaki T, Fukasawa H, Suzuki H, et al. Intrarenal RAS activity and urinary angiotensinogen excretion in anti-thymocyte serum nephritis rats. Am J Physiol Ren Physiol. 2008;295:F1512–8.
Isobe S, Ohashi N, Ishigaki S, Tsuji T, Sakao Y, Kato A, et al. Augmented circadian rhythm of the intrarenal renin-angiotensin systems in anti-thymocyte serum nephritis rats. Hypertens Res. 2016;39:312–20.
Kamiyama M, Urushihara M, Morikawa T, Konishi Y, Imanishi M, Nishiyama A, et al. Oxidative stress/angiotensinogen/renin-angiotensin system axis in patients with diabetic nephropathy. Int J Mol Sci. 2013;14:23045–62.
Kobori H, Nishiyama A. Effects of tempol on renal angiotensinogen production in Dahl salt-sensitive rats. Biochem Biophys Res Commun. 2004;315:746–50.
Souchet T, Brée F, Baatard R, Fontenaille C, D’Athis P, Tillement JP, et al. Impaired regulation of beta 2-adrenergic receptor density in mononuclear cells during chronic renal failure. Biochem Pharmacol. 1986;35:2513–9.
Nagtegaal JE, Smits MG, Kerkhof GA, Pandi-Perumal SR. Chronobiological, clinical and pharmacological aspects of melatonin in human circadian rhythm dysfunction. In: Haldar C, Singaravel M, Kumar Maitra S, editors. Treatise on pineal gland and melatonin. Enfield: Science Publishers; 2002. p. 461–89.
Ozbek E, Ilbey Y, Ozbek M, Simsek A, Cekmen M, Somay A. Melatonin attenuates unilateral ureteral obstruction-induced renal injury by reducing oxidative stress, iNOS, MAPK, and NF-kB expression. J Endourol. 2009;23:1165–73.
Nava M, Quiroz Y, Vaziri N, Rodriguez-Iturbe B. Melatonin reduces renal interstitial inflammation and improves hypertension in spontaneously hypertensive rats. Am J Physiol Ren Physiol. 2003;284:F447–54.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–305.
Drey N, Roderick P, Mullee M, Rogerson M. A population-based study of the incidence and outcomes of diagnosed chronic kidney disease. Am J Kidney Dis. 2003;42:677–84.
Renal Data System. USRDS 2003 annual data report: atlas of end-stage renal disease in the United States. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2003.
Imai E, Horio M, Watanabe T, Iseki K, Yamagata K, Hara S, et al. Prevalence of chronic kidney disease in the Japanese general population. Clin Exp Nephrol. 2009;13:621–30.
Acuña D, Soler A, García-Torres L, Vargas F, García del Río C, Quesada T, et al. Inhibition of the renin-angiotensin system by pinealectomy in female rats. Rev Esp Fisiol. 1982;38:251–5.
Baltatu O, Lippoldt A, Hansson A, Ganten D, Bader M. Local renin-angiotensin system in the pineal gland. Brain Res Mol Brain Res. 1998;54:237–42.
Baltatu O, Afeche SC, José dos Santos SH, Campos LA, Barbosa R, Michelini LC, et al. Locally synthesized angiotensin modulates pineal melatonin generation. J Neurochem. 2002;80:328–34.
Campos LA, Cipolla-Neto J, Amaral FG, Michelini LC, Bader M, Baltatu OC. The angiotensin-melatonin axis. Int J Hypertens. 2013;2013:521783.
Ishigaki S, Ohashi N, Isobe S, Tsuji N, Iwakura T, Ono M, et al. Impaired endogenous nighttime melatonin secretion relates to intrarenal renin-angiotensin system activation and renal damage in patients with chronic kidney disease. Clin Exp Nephrol. 2016;20:878–84.
Ishigaki S, Ohashi N, Matsuyama T, Isobe S, Tsuji N, Iwakura T, et al. Melatonin ameliorates intrarenal renin-angiotensin system in a 5/6 nephrectomy rat model. Clin Exp Nephrol. 2018;22:539–49.
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Ohashi, N., Ishigaki, S. & Isobe, S. The pivotal role of melatonin in ameliorating chronic kidney disease by suppression of the renin–angiotensin system in the kidney. Hypertens Res 42, 761–768 (2019). https://doi.org/10.1038/s41440-018-0186-2
- Chronic kidney disease
- reactive oxygen species
- renin-angiotensin system
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