Clinical and Experimental Nephrology

, Volume 20, Issue 6, pp 878–884 | Cite as

Impaired endogenous nighttime melatonin secretion relates to intrarenal renin–angiotensin system activation and renal damage in patients with chronic kidney disease

  • Sayaka Ishigaki
  • Naro OhashiEmail author
  • Shinsuke Isobe
  • Naoko Tsuji
  • Takamasa Iwakura
  • Masafumi Ono
  • Yukitoshi Sakao
  • Takayuki Tsuji
  • Akihiko Kato
  • Hiroaki Miyajima
  • Hideo Yasuda
Original Article



Activation of the intrarenal renin–angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti-adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients.


We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6-sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U-AGT), and urinary albumin (U-Alb).


Patients’ U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U-aMT6s levels were significantly associated with U-AGT (β = −0.31, p = 0.044) and U-Alb (β = −0.25, p = 0.025) only at night.


Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients.


Melatonin Urinary 6-sulphatoxymelatonin Intrarenal renin–angiotensin system Urinary angiotensinogen Blood pressure Chronic kidney disease 




Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.


  1. 1.
    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;59:251–7.CrossRefGoogle Scholar
  2. 2.
    Navar LG, Harrison-Bernard LM, Nishiyama A, Kobori H. Regulation of intrarenal angiotensin II in hypertension. Hypertension. 2002;39:316–22.CrossRefGoogle Scholar
  3. 3.
    Kobori H, Ohashi N, Katsurada A, Miyata K, Satou R, Saito T, Yamamoto T. Urinary angiotensinogen as a potential biomarker of severity of chronic renal disease. J Am Soc Hypertens. 2008;2:349–54.CrossRefGoogle Scholar
  4. 4.
    Isobe S, Ohashi N, Fujikura T, Tsuji T, Sakao Y, Yasuda H, Kato A, Miyajima H, Fujigaki Y. Disturbed circadian rhythm of the intrarenal renin–angiotensin system: relevant to nocturnal hypertension and renal damage. Clin Exp Nephrol. 2015;19:231–9.CrossRefGoogle Scholar
  5. 5.
    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.CrossRefGoogle Scholar
  6. 6.
    Ohashi N, Urushihara M, Kobori H. Activated intrarenal reactive oxygen species and renin angiotensin in IgA nephropathy. Minerva Urol Nefrol. 2009;61:55–66.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Kamiyama M, Urushihara M, Morikawa T, Konishi Y, Imanishi M, Nishiyama A, Kobori H. Oxidative stress/angiotensinogen/renin–angiotensin system axis in patients with diabetes nephropathy. Int J Mol Sci. 2013;14:23045–62.CrossRefGoogle Scholar
  8. 8.
    Cao W, Li A, Wang L, Zhou Z, Su Z, Bin W, Wilcox CS, Hou FF. A salt-induced reno-cerebral reflex activates renin–angiotensin systems and promotes CKD progression. J Am Soc Nephrol. 2015;26:1619–33.CrossRefGoogle Scholar
  9. 9.
    Graciano ML, de Cavaglieri RC, Dellê H, Dominguez WV, Casarini DE, Malheiros DM, Noronha IL. Intrarenal renin–angiotensin system is upregulated in experimental model of progressive renal disease induced by chronic inhibition of nitric oxide synthesis. J Am Soc Nephrol. 2004;15:1805–15.CrossRefGoogle Scholar
  10. 10.
    Rincón J, Correia D, Arcaya JL, Finol E, Fernández A, Pérez M, Yaguas K, Talavera E, Chávez M, Summer R, Romero F. Role of angiotensin II type 1 receptor on renal NAD(P)H oxidase, oxidative stress and inflammation in nitric oxide inhibition induced-hypertension. Life Sci; 124:81–90.Google Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    Kalra S, Agrawal S, Sahay M. The reno-pineal axis: a novel role for melatonin. Indian J Endocrinol Metab. 2012;16:192–4.CrossRefGoogle Scholar
  13. 13.
    Simko F, Reiter RJ, Pechanova O, Paulis L. Experimental models of melatonin-deficient hypertension. Front Biosci. 2013;18:616–25.CrossRefGoogle Scholar
  14. 14.
    Nava M, Quiroz Y, Vaziri N, Rodriguez-Iturbe B. Melatonin reduces renal interstitial inflammation and improves hypertension in spontaneously hypertensive rats. Am J Physiol Renal Physiol. 2003;284:F447–54.CrossRefGoogle Scholar
  15. 15.
    Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995;346:541–4.CrossRefGoogle Scholar
  16. 16.
    Ritzenthaler T, Nighoghossian N, Berthiller J, Schott AM, Cho TH, Derex L, Brun J, Trouillas P, Claustrat B. Nocturnal urine melatonin and 6-sulphatoxymelatonin excretion at the acute stage of ischaemic stroke. J Pineal Res. 2009;46:349–52.CrossRefGoogle Scholar
  17. 17.
    Deacon SJ, Arendt J. Phase-shifts in melatonin, 6-sulphatoxymelatonin and alertness rythms after treatment with moderately bright light at night. Clin Endocrinol. 1994;40:413–20.CrossRefGoogle Scholar
  18. 18.
    Katsurada A, Hagiwara Y, Miyashita K, Satou R, Miyata K, Ohashi N, Navar LG, Kobori H. Novel sandwich ELISA for human angiotensinogen. Am J Physiol Renal Physiol. 2007;293:956–60.CrossRefGoogle Scholar
  19. 19.
    Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A. Revised equation for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.CrossRefGoogle Scholar
  20. 20.
    Atilgan D, Parlaktas BS, Uluocak N, Erdemir F, Firat F, Erkorkmaz U, Saylan O. Effects of melatonin on partial unilateral ureteral obstruction induced oxidative injury in rat kidney. Urol Ann. 2012;4:89–93.CrossRefGoogle Scholar
  21. 21.
    ParlakpInar H, Sahna E, Ozer MK, Ozugurlu F, Vardi N, Acet A. Physiological and pharmacological concentrations of melatonin protect against cisplatin-induced acute renal injury. J Pineal Res. 2002;33:161–6.CrossRefGoogle Scholar
  22. 22.
    Husain K, Hernandez W, Ansari RA, Ferder L. Inflammation, oxidative stress and renin angiotensin system in atherosclerosis. World J Biol Chem. 2015;26:209–17.CrossRefGoogle Scholar
  23. 23.
    Simko F, Pechanova O. Potential roles of melatonin and chronotherapy among the new trends in hypertension treatment. J Pineal Res. 2009;47:127–33.CrossRefGoogle Scholar
  24. 24.
    K-Laflamme A, Wu L, Foucart S, de Champlain J. Impaired basal sympathetic tone and alpha 1-adrenergic responsiveness in association with the hypotensive effect of melatonin in spontaneously hypertensive rats. Am J Hypertens. 1998;11:219–29.CrossRefGoogle Scholar
  25. 25.
    Girouard H, Chulak C, LeJossec M, Lamontagne D, de Champlain J. Chronic antioxidant treatment improves sympathetic functions and beta-adrenergic pathway in the spontaneously hypertensive rats. J Hypertens. 2003;21:179–88.CrossRefGoogle Scholar
  26. 26.
    Cagnacci A, Arangino S, Angiolucci M, Maschio E, Melis GB. Influences of melatonin administration on the circulation of women. Am J Physiol. 1998;274:R335–8.PubMedGoogle Scholar
  27. 27.
    Jonas M, Garfinkel D, Zisapel N, Laudon M, Grossman E. Impaired nocturnal melatonin secretion in non-dipper hypertensive patients. Blood Press. 2003;12:19–24.PubMedGoogle Scholar
  28. 28.
    Scheer FA, Van Montfrans GA, Van Someren EJ, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension. 2004;43:192–7.CrossRefGoogle Scholar
  29. 29.
    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.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Koch BC, Van Der Putten K, Van Someren EJ, Wielders JP, TerWee PM, Nagtegaal JE, Gaillard CA. Impairment of endogenous melatonin rhythm is related to the degree of chronic kidney disease (CREAM study). Nephrol Dial Transpl. 2010;25:513–9.CrossRefGoogle Scholar
  31. 31.
    Baskett JJ, Cockrem JF, Antunovich TA. Sulphatoxymelatonin excretion in older people: relationship to plasma melatonin and renal function. J Pineal Res. 1998;24:58–61.CrossRefGoogle Scholar
  32. 32.
    Graham C, Cook MR, Kavet R, Sastre A, Smith DK. Prediction of nocturnal plasma melatonin from morning urinary measures. J Pineal Res. 1998;24:230–8.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Nephrology 2016

Authors and Affiliations

  • Sayaka Ishigaki
    • 1
  • Naro Ohashi
    • 1
    Email author
  • Shinsuke Isobe
    • 1
  • Naoko Tsuji
    • 1
  • Takamasa Iwakura
    • 1
  • Masafumi Ono
    • 1
  • Yukitoshi Sakao
    • 2
  • Takayuki Tsuji
    • 1
  • Akihiko Kato
    • 2
  • Hiroaki Miyajima
    • 1
  • Hideo Yasuda
    • 1
  1. 1.Internal Medicine 1Hamamatsu University School of MedicineHamamatsuJapan
  2. 2.Blood Purification UnitHamamatsu University School of MedicineHamamatsuJapan

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