Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Disruption of circadian rhythm as a potential pathogenesis of nocturia

Abstract

Increasing evidence suggested the multifactorial nature of nocturia, but the true pathogenesis of this condition still remains to be elucidated. Contemporary clinical medications are mostly symptom based, aimed at either reducing nocturnal urine volume or targeting autonomic receptors within the bladder to facilitate urine storage. The day–night switch of the micturition pattern is controlled by circadian clocks located both in the central nervous system and in the peripheral organs. Arousal threshold and secretion of melatonin and vasopressin increase at night-time to achieve high-quality sleep and minimize nocturnal urine production. In response to the increased vasopressin, the kidney reduces the glomerular filtration rate and facilitates the reabsorption of water. Synchronously, in the bladder, circadian oscillation of crucial molecules occurs to reduce afferent sensory input and maintain sufficient bladder capacity during the night sleep period. Thus, nocturia might occur as a result of desynchronization in one or more of these circadian regulatory mechanisms. Disrupted rhythmicity of the central nervous system, kidney and bladder (known as the brain–kidney–bladder circadian axis) contributes to the pathogenesis of nocturia. Novel insights into the chronobiological nature of nocturia will be crucial to promote a revolutionary shift towards effective therapeutics targeting the realignment of the circadian rhythm.

Key points

  • Growing evidence has shown that disrupted rhythmicity of the central nervous system, kidney and bladder (the brain–kidney–bladder circadian axis) contributes to the pathogenesis of nocturia.

  • The daily rhythm of human behaviour and physiology is regulated by the transcription–translation feedback loop, which exists both in the brain and in peripheral metabolic tissues, consisting of opposite transcriptional activators (CLOCK and BMAL1) and repressors (PER and CRY).

  • Disruption of the central clock in the suprachiasmatic nucleus and neuroendocrine system leads to nocturia through impaired sleep quality and misaligned release of hormones such as melatonin and arginine vasopressin.

  • Most physiological renal processes, such as urine secretion and water reabsorption, follow a circadian pattern of activity; disruptions of this pattern can cause nocturia.

  • The circadian expression of peripheral clock genes in the bladder leads to time-dependent variations of bladder sensation and excitability, which can be disorganized under pathophysiological conditions contributing to nocturia onset.

  • Expanding knowledge of the molecular basis of circadian regulation and dysregulation within the brain–kidney–bladder circadian axis will help to develop strategies for the prevention, management and treatment of nocturia based on chronobiology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The transcription–translation feedback loop and the brain–kidney–bladder circadian axis.
Fig. 2: PER1-mediated circadian control of the nephron.
Fig. 3 : Circadian modulation of urothelial receptors and signals in regulation of diurnal rhythmic bladder function.

Similar content being viewed by others

References

  1. Hashim, H. et al. International Continence Society (ICS) report on the terminology for nocturia and nocturnal lower urinary tract function. Neurourol. Urodyn. 38, 499–508 (2019).

    Article  PubMed  Google Scholar 

  2. Dani, H., Esdaille, A. & Weiss, J. P. Nocturia: aetiology and treatment in adults. Nat. Rev. Urol. 13, 573–583 (2016).

    Article  PubMed  Google Scholar 

  3. Hashim, H. & Drake, M. J. Basic concepts in nocturia, based on International Continence Society standards in nocturnal lower urinary tract function. Neurourol. Urodyn. 37, S20–S24 (2018).

    Article  PubMed  Google Scholar 

  4. Nakagawa, H. et al. Impact of nocturia on bone fracture and mortality in older individuals: a Japanese Longitudinal Cohort Study. J. Urol. 184, 1413–1418 (2010).

    Article  PubMed  Google Scholar 

  5. Obayashi, K., Saeki, K., Negoro, H. & Kurumatani, N. Nocturia increases the incidence of depressive symptoms: a longitudinal study of the HEIJO-KYO cohort. BJU Int. 120, 280–285 (2017).

    Article  PubMed  Google Scholar 

  6. Funada, S. et al. Impact of nocturia on mortality: the Nagahama Study. J. Urol. 204, 996–1002 (2020).

    Article  PubMed  Google Scholar 

  7. Bliwise, D. L., Wagg, A. & Sand, P. K. Nocturia: a highly prevalent disorder with multifaceted consequences. Urology 133S, 3–13 (2019).

    Article  PubMed  Google Scholar 

  8. Azuero, J. et al. Potential associations of adult nocturia. Results from a national prevalence study. Neurourol. Urodyn. 40, 819–828 (2021).

    Article  CAS  PubMed  Google Scholar 

  9. Lazar, J. M. et al. Nocturia is associated with high atherosclerotic cardiovascular disease risk in women: results from the National Health and Nutrition Examination Survey. J. Community Health 46, 854–860 (2021).

    Article  PubMed  Google Scholar 

  10. Bosch, J. L. H. R. & Weiss, J. P. The prevalence and causes of nocturia. J. Urol. 189, S86–S92 (2013).

    Article  PubMed  Google Scholar 

  11. Malde, S. et al. Incidence of nocturia in men with lower urinary tract symptoms associated with benign prostatic enlargement and outcomes after medical treatment: results from the Evolution European Association of Urology Research Foundation Prospective Multinational Registry. Eur. Urol. Focus. 7, 178–185 (2021).

    Article  PubMed  Google Scholar 

  12. Song, Q. X. et al. The characteristics and risk factors of healthcare-seeking men with lower urinary tract symptoms in China: initial report from the POInT group. Neurourol. Urodyn. 40, 1740–1753 (2021).

    Article  CAS  PubMed  Google Scholar 

  13. Daugherty, M., Ginzburg, N. & Byler, T. Prevalence of nocturia in United States women: results from National Health and Nutrition Examination Survey. Female Pelvic Med. Reconstr. Surg. 27, e52–e58 (2021).

    Article  PubMed  Google Scholar 

  14. Dutoglu, E. et al. Nocturia and its clinical implications in older women. Arch. Gerontol. Geriatr. 85, 103917 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. Bower, W. F. et al. The association between nocturia, hormonal symptoms and bladder parameters in women: an observational study. BJOG 129, 812–819 (2022).

    Article  CAS  PubMed  Google Scholar 

  16. Song, Q., Abrams, P. & Sun, Y. Beyond prostate, beyond surgery and beyond urology: The “3Bs” of managing non-neurogenic male lower urinary tract symptoms. Asian J. Urol. 6, 169–173 (2019).

    Article  PubMed  Google Scholar 

  17. Chapple, C. R. et al. Lower urinary tract symptoms revisited: a broader clinical perspective. Eur. Urol. 54, 563–569 (2008).

    Article  PubMed  Google Scholar 

  18. Abrams, P. New words for old: lower urinary tract symptoms for “prostatism”. BMJ 308, 929–930 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Haga, N. et al. Postoperative urinary incontinence exacerbates nocturia-specific quality of life after robot-assisted radical prostatectomy. Int. J. Urol. 23, 873–878 (2016).

    Article  PubMed  Google Scholar 

  20. Seki, N., Yuki, K., Takei, M., Yamaguchi, A. & Naito, S. Analysis of the prognostic factors for overactive bladder symptoms following surgical treatment in patients with benign prostatic obstruction. Neurourol. Urodyn. 28, 197–201 (2009).

    Article  PubMed  Google Scholar 

  21. Smith, A. L. & Wein, A. J. Outcomes of pharmacological management of nocturia with non-antidiuretic agents: does statistically significant equal clinically significant? BJU Int. 107, 1550–1554 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Araujo, A. B. et al. Sleep related problems and urological symptoms: testing the hypothesis of bidirectionality in a longitudinal, population based study. J. Urol. 191, 100–106 (2014).

    Article  PubMed  Google Scholar 

  23. Negoro, H. et al. Risk analyses of nocturia on incident poor sleep and vice versa: the Nagahama study. Sci. Rep. 13, 9495 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Djavan, B., Milani, S., Davies, J. & Bolodeoku, J. The impact of tamsulosin oral controlled absorption system (OCAS) on nocturia and the quality of sleep: preliminary results of a pilot study. Eur. Urol. Suppl. 4, 61–68 (2005).

    Article  CAS  Google Scholar 

  25. Schneider, T. & Stanley, N. Impact of nocturia on sleep and energy. Eur. Urol. Suppl. 6, 585–593 (2007).

    Article  Google Scholar 

  26. Hirshkowitz, M. Normal human sleep: an overview. Med. Clin. N. Am. 88, 551–565 (2004).

    Article  PubMed  Google Scholar 

  27. Stanley, N. The physiology of sleep and the impact of ageing. Eur. Urol. Suppl. 3, 17–23 (2005).

    Article  Google Scholar 

  28. Papworth, E. et al. Association of sleep disorders with nocturia: a systematic review and nominal group technique consensus on primary care assessment and treatment. Eur. Urol. Focus. 8, 42–51 (2022).

    Article  PubMed  Google Scholar 

  29. Umlauf, M. G. & Chasens, E. R. Sleep disordered breathing and nocturnal polyuria: nocturia and enuresis. Sleep. Med. Rev. 7, 403–411 (2003).

    Article  PubMed  Google Scholar 

  30. Umlauf, M. G. et al. Obstructive sleep apnea, nocturia and polyuria in older adults. Sleep 27, 139–144 (2004).

    Article  PubMed  Google Scholar 

  31. Doyle-McClam, M., Shahid, M. H., Sethi, J. M. & Koo, P. Nocturia in women with obstructive sleep apnea. Am. J. Lifestyle Med. 15, 260–268 (2021).

    Article  PubMed  Google Scholar 

  32. McInnis, R. P., Dodds, E. B., Johnsen, J., Auerbach, S. & Pyatkevich, Y. CPAP treats enuresis in adults with obstructive sleep apnea. J. Clin. Sleep. Med. 13, 1209–1212 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Weiss, J. P. & Everaert, K. Management of nocturia and nocturnal polyuria. Urology 133S, 24–33 (2019).

    Article  PubMed  Google Scholar 

  34. Tyagi, S. & Chancellor, M. B. Nocturnal polyuria and nocturia. Int. Urol. Nephrol. 55, 1395–1401 (2023).

    Article  PubMed  Google Scholar 

  35. van Kerrebroeck, P. et al. The standardisation of terminology in nocturia: report from the standardisation sub-committee of the International Continence Society. Neurourol. Urodyn. 21, 179–183 (2002).

    Article  PubMed  Google Scholar 

  36. Weiss, J. P., van Kerrebroeck, P. E., Klein, B. M. & Norgaard, J. P. Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia. J. Urol. 186, 1358–1363 (2011).

    Article  PubMed  Google Scholar 

  37. Goessaert, A. S., Krott, L., Hoebeke, P., Vande Walle, J. & Everaert, K. Diagnosing the pathophysiologic mechanisms of nocturnal polyuria. Eur. Urol. 67, 283–288 (2015).

    Article  PubMed  Google Scholar 

  38. Hervé, F. et al. Is our current understanding and management of nocturia allowing improved care? International Consultation on Incontinence‐Research Society 2018. Neurourol. Urodyn. 38, S127–S133 (2019).

    Article  PubMed  Google Scholar 

  39. Emeruwa, C. J., Epstein, M. R., Michelson, K. P., Monaghan, T. F. & Weiss, J. P. Prevalence of the nocturnal polyuria syndrome in men. Neurourol. Urodyn. 39, 1732–1736 (2020).

    Article  PubMed  Google Scholar 

  40. Drangsholt, S. et al. Diagnosis and management of nocturia in current clinical practice: who are nocturia patients, and how do we treat them? World J. Urol. 37, 1389–1394 (2019).

    Article  PubMed  Google Scholar 

  41. Gulur, D. M., Mevcha, A. M. & Drake, M. J. Nocturia as a manifestation of systemic disease. BJU Int. 107, 702–713 (2011).

    Article  PubMed  Google Scholar 

  42. Ohishi, M., Kubozono, T., Higuchi, K. & Akasaki, Y. Hypertension, cardiovascular disease, and nocturia: a systematic review of the pathophysiological mechanisms. Hypertens. Res. 44, 733–739 (2021).

    Article  CAS  PubMed  Google Scholar 

  43. Everaert, K. et al. International Continence Society consensus on the diagnosis and treatment of nocturia. Neurourol. Urodyn. 38, 478–498 (2019).

    Article  PubMed  Google Scholar 

  44. Fine, N. D., Weiss, J. P. & Wein, A. J. Nocturia: consequences, classification, and management. F1000Res. 6, 1627–1627 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Drangsholt, S. et al. Diagnosis and management of nocturia in current clinical practice: who are nocturia patients, and how do we treat them? World J. Urol., 37, 1389–1394 (2019).

    Article  PubMed  Google Scholar 

  46. Gordon, D. J., Emeruwa, C. J. & Weiss, J. P. Management strategies for nocturia. Curr. Urol. Rep. 20, 75 (2019).

    Article  PubMed  Google Scholar 

  47. Yap, T. L., Brown, C., Cromwell, D. A., van der Meulen, J. & Emberton, M. The impact of self-management of lower urinary tract symptoms on frequency-volume chart measures. BJU Int. 104, 1104–1108 (2009).

    Article  PubMed  Google Scholar 

  48. Robinson, D., Giarenis, I. & Cardozo, L. You are what you eat: the impact of diet on overactive bladder and lower urinary tract symptoms. Maturitas 79, 8–13 (2014).

    Article  CAS  PubMed  Google Scholar 

  49. Robinson, D., Hanna-Mitchell, A., Rantell, A., Thiagamoorthy, G. & Cardozo, L. Are we justified in suggesting change to caffeine, alcohol, and carbonated drink intake in lower urinary tract disease? Report from the ICI-RS 2015. Neurourol. Urodyn. 36, 876–881 (2017).

    Article  PubMed  Google Scholar 

  50. Majumdar, A., Hassan, I., Saleh, S. & Toozs-Hobson, P. Inpatient bladder retraining: is it beneficial on its own? Int. Urogynecol. J. 21, 657–663 (2010).

    Article  PubMed  Google Scholar 

  51. Kaga, K. et al. The efficacy of compression stockings on patients with nocturia: a single-arm pilot study. Cureus 14, e28603 (2022).

    PubMed  PubMed Central  Google Scholar 

  52. Miyazato, M. et al. Effect of continuous positive airway pressure on nocturnal urine production in patients with obstructive sleep apnea syndrome. Neurourol. Urodyn. 36, 376–379 (2017).

    Article  CAS  PubMed  Google Scholar 

  53. Sakalis, V. I. et al. Medical treatment of nocturia in men with lower urinary tract symptoms: systematic review by the European Association of Urology Guidelines Panel for Male Lower Urinary Tract Symptoms. Eur. Urol. 72, 757–769 (2017).

    Article  PubMed  Google Scholar 

  54. Garrison, S. R. et al. Tolerability of bedtime diuretics: a prospective cohort analysis. BMJ Open 13, e068188 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Hillier, P., Knapp, M. S. & Cove-Smith, R. Circadian variations in urine excretion in chronic renal failure. Q. J. Med. 49, 461–478 (1980).

    CAS  PubMed  Google Scholar 

  56. Singh, R. K., Bansal, A., Bansal, S. K. & Rai, S. P. Circadian rhythms of common laboratory profiles in serum and urine of healthy Indians. Prog. Clin. Biol. Res. 341B, 559–566 (1990).

    CAS  PubMed  Google Scholar 

  57. Asplund, R. & Aberg, H. E. Micturition habits of older people. Voiding frequency and urine volumes. Scand. J. Urol. Nephrol. 26, 345–349 (1992).

    Article  CAS  PubMed  Google Scholar 

  58. Duffy, J. F., Scheuermaier, K. & Loughlin, K. R. Age-related sleep disruption and reduction in the circadian rhythm of urine output: contribution to nocturia? Curr. Aging Sci. 9, 34–43 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Smolensky, M. H., Hermida, R. C., Reinberg, A., Sackett-Lundeen, L. & Portaluppi, F. Circadian disruption: new clinical perspective of disease pathology and basis for chronotherapeutic intervention. Chronobiol. Int. 33, 1101–1119 (2016).

    Article  PubMed  Google Scholar 

  60. Patke, A., Young, M. W. & Axelrod, S. Molecular mechanisms and physiological importance of circadian rhythms. Nat. Rev. Mol. Cell Biol. 21, 67–84 (2020).

    Article  CAS  PubMed  Google Scholar 

  61. Greco, C. M. & Sassone-Corsi, P. Circadian blueprint of metabolic pathways in the brain. Nat. Rev. Neurosci. 20, 71–82 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lu, Q. & Kim, J. Y. Mammalian circadian networks mediated by the suprachiasmatic nucleus. FEBS J. 289, 6589–6604 (2022).

    Article  CAS  PubMed  Google Scholar 

  63. Panda, S. Circadian physiology of metabolism. Science 354, 1008–1015 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bass, J. Circadian topology of metabolism. Nature 491, 348–356 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Bass, J. & Takahashi, J. S. Circadian integration of metabolism and energetics. Science 330, 1349–1354 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dibner, C., Schibler, U. & Albrecht, U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu. Rev. Physiol. 72, 517–549 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Asher, G. & Schibler, U. Crosstalk between components of circadian and metabolic cycles in mammals. Cell Metab. 13, 125–137 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Gumz, M. L. et al. Toward precision medicine: circadian rhythm of blood pressure and chronotherapy for hypertension — 2021 NHLBI Workshop Report. Hypertension 80, 503–522 (2023).

    Article  CAS  PubMed  Google Scholar 

  69. Stenvers, D. J., Scheer, F., Schrauwen, P., la Fleur, S. E. & Kalsbeek, A. Circadian clocks and insulin resistance. Nat. Rev. Endocrinol. 15, 75–89 (2019).

    Article  PubMed  Google Scholar 

  70. Lekkas, D. & Paschos, G. K. The circadian clock control of adipose tissue physiology and metabolism. Auton. Neurosci. 219, 66–70 (2019).

    Article  CAS  PubMed  Google Scholar 

  71. McCauley, J. P. et al. Circadian modulation of neurons and astrocytes controls synaptic plasticity in hippocampal area CA1. Cell Rep. 33, 108255 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gerstner, J. R. & Yin, J. C. Circadian rhythms and memory formation. Nat. Rev. Neurosci. 11, 577–588 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Shiju, S. & Sriram, K. Multi-scale modeling of the circadian modulation of learning and memory. PLoS ONE 14, e0219915 (2019).

    Article  Google Scholar 

  74. Crock, L. W. et al. Metabotropic glutamate receptor 5 (mGluR5) regulates bladder nociception. Mol. Pain. 8, 20 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ochodnicky, P. et al. Bradykinin modulates spontaneous nerve growth factor production and stretch-induced ATP release in human urothelium. Pharmacol. Res. 70, 147–154 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Uy, J. et al. Glutamatergic mechanisms involved in bladder overactivity and pudendal neuromodulation in cats. J. Pharmacol. Exp. Ther. 362, 53–58 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Yokoyama, O., Yoshiyama, M., Namiki, M. & de Groat, W. C. Role of the forebrain in bladder overactivity following cerebral infarction in the rat. Exp. Neurol. 163, 469–476 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Xie, Z. et al. A review of sleep disorders and melatonin. Neurol. Res. 39, 559–565 (2017).

    Article  CAS  PubMed  Google Scholar 

  79. Yanar, K., Simsek, B. & Cakatay, U. Integration of melatonin related redox homeostasis, aging, and circadian rhythm. Rejuvenation Res. 22, 409–419 (2019).

    Article  PubMed  Google Scholar 

  80. Rutter, J., Reick, M. & McKnight, S. L. Metabolism and the control of circadian rhythms. Annu. Rev. Biochem. 71, 307–331 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Huang, W., Ramsey, K. M., Marcheva, B. & Bass, J. Circadian rhythms, sleep, and metabolism. J. Clin. Invest. 121, 2133–2141 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Boivin, D. B. & Boudreau, P. Impacts of shift work on sleep and circadian rhythms. Pathol. Biol. 62, 292–301 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Gabriel, B. M. & Zierath, J. R. Circadian rhythms and exercise — re-setting the clock in metabolic disease. Nat. Rev. Endocrinol. 15, 197–206 (2019).

    Article  PubMed  Google Scholar 

  84. Boivin, D. B., Boudreau, P. & Kosmadopoulos, A. Disturbance of the circadian system in shift work and its health impact. J. Biol. Rhythm. 37, 3–28 (2022).

    Article  CAS  Google Scholar 

  85. Bolsius, Y. G. et al. The role of clock genes in sleep, stress and memory. Biochem. Pharmacol. 191, 114493 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Huang, Y., Wang, H., Li, Y., Tao, X. & Sun, J. Poor sleep quality is associated with dawn phenomenon and impaired circadian clock gene expression in subjects with type 2 diabetes mellitus. Int. J. Endocrinol. 2017, 4578973 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Matsumoto, T. et al. Nocturia and increase in nocturnal blood pressure: the Nagahama study. J. Hypertens. 36, 2185–2192 (2018).

    Article  CAS  PubMed  Google Scholar 

  88. Furukawa, S. et al. Nocturia and prevalence of depressive symptoms in Japanese adult patients with type 2 diabetes mellitus: the Dogo study. Can. J. Diabetes 42, 51–55 (2018).

    Article  PubMed  Google Scholar 

  89. Juul, K. V., Jessen, N., Bliwise, D. L., van der Meulen, E. & Norgaard, J. P. Delaying time to first nocturnal void may have beneficial effects on reducing blood glucose levels. Endocrine 53, 722–729 (2016).

    Article  CAS  PubMed  Google Scholar 

  90. Kim, J. W. Effect of shift work on nocturia. Urology 87, 153–160 (2016).

    Article  PubMed  Google Scholar 

  91. Leng, Y., Musiek, E. S., Hu, K., Cappuccio, F. P. & Yaffe, K. Association between circadian rhythms and neurodegenerative diseases. Lancet Neurol. 18, 307–318 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Videnovic, A., Lazar, A. S., Barker, R. A. & Overeem, S. ‘The clocks that time us’ — circadian rhythms in neurodegenerative disorders. Nat. Rev. Neurol. 10, 683–693 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Leng, Y. et al. Excessive daytime sleepiness, objective napping and 11-year risk of Parkinson’s disease in older men. Int. J. Epidemiol. 47, 1679–1686 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Walsh, C. M. et al. Weaker circadian activity rhythms are associated with poorer executive function in older women. Sleep 37, 2009–2016 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Rogers-Soeder, T. S. et al. Rest-activity rhythms and cognitive decline in older men: the osteoporotic fractures in men sleep study. J. Am. Geriatr. Soc. 66, 2136–2143 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Bokenberger, K. et al. Association between sleep characteristics and incident dementia accounting for baseline cognitive status: a prospective population-based study. J. Gerontol. A Biol. Sci. Med. Sci. 72, 134–139 (2017).

    Article  PubMed  Google Scholar 

  97. Cronin, P. et al. Circadian alterations during early stages of Alzheimer’s disease are associated with aberrant cycles of DNA methylation in BMAL1. Alzheimers Dement. 13, 689–700 (2017).

    Article  PubMed  Google Scholar 

  98. Musiek, E. S. & Holtzman, D. M. Mechanisms linking circadian clocks, sleep, and neurodegeneration. Science 354, 1004–1008 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Verma, A. K., Singh, S. & Rizvi, S. I. Aging, circadian disruption and neurodegeneration: Interesting interplay. Exp. Gerontol. 172, 112076 (2023).

    Article  PubMed  Google Scholar 

  100. Sengiku, A. et al. Circadian coordination of ATP release in the urothelium via connexin43 hemichannels. Sci. Rep. 8, 1996 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Negoro, H. et al. Involvement of urinary bladder Connexin43 and the circadian clock in coordination of diurnal micturition rhythm. Nat. Commun. 3, 809 (2012).

    Article  PubMed  Google Scholar 

  102. Ihara, T. et al. The Clock mutant mouse is a novel experimental model for nocturia and nocturnal polyuria. Neurourol. Urodyn. 36, 1034–1038 (2016).

    Article  PubMed  Google Scholar 

  103. Noh, J. Y. et al. Circadian rhythms in urinary functions: possible roles of circadian clocks? Int. Neurourol. J. 15, 64–73 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Goldman, R. Studies in diurnal variation of water and electrolyte excretion; nocturnal diuresis of water and sodium in congestive cardiac failure and cirrhosis of the liver. J. Clin. Invest. 30, 1191–1199 (1951).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Weiss, J. P. & Blaivas, J. G. Nocturia. J. Urol. 163, 5–12 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Sakakibara, R. et al. Nocturnal polyuria with abnormal circadian rhythm of plasma arginine vasopressin in post-stroke patients. Intern. Med. 44, 281–284 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Adler, D. et al. Clinical presentation and comorbidities of obstructive sleep apnea-COPD overlap syndrome. PLoS ONE 15, e0235331 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Asplund, R. & Aberg, H. Diurnal variation in the levels of antidiuretic hormone in the elderly. J. Intern. Med. 229, 131–134 (1991).

    Article  CAS  PubMed  Google Scholar 

  109. Hoshiyama, F. et al. The impact of obstructive sleep apnea syndrome on nocturnal urine production in older men with nocturia. Urology 84, 892–896 (2014).

    Article  PubMed  Google Scholar 

  110. Forsling, M. L., Montgomery, H., Halpin, D., Windle, R. J. & Treacher, D. F. Daily patterns of secretion of neurohypophysial hormones in man: effect of age. Exp. Physiol. 83, 409–418 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Potter, G. D. et al. Circadian rhythm and sleep disruption: causes, metabolic consequences, and countermeasures. Endocr. Rev. 37, 584–608 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zisapel, N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br. J. Pharmacol. 175, 3190–3199 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Brzezinski, A., Rai, S., Purohit, A. & Pandi-Perumal, S. R. Melatonin, clock genes, and mammalian reproduction: what is the link? Int. J. Mol. Sci. 22, 13240 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Bian, J., Wang, Z., Dong, Y., Cao, J. & Chen, Y. Role of BMAL1 and CLOCK in regulating the secretion of melatonin in chick retina under monochromatic green light. Chronobiol. Int. 37, 1677–1692 (2020).

    Article  CAS  PubMed  Google Scholar 

  115. Burke, C. A., Nitti, V. W. & Stothers, L. Melatonin and melatonin receptor agonists in the treatment of nocturia: a systematic review. Neurourol. Urodyn. 43, 826–839 (2024).

    Article  PubMed  Google Scholar 

  116. Liu, J. et al. MT1 and MT2 melatonin receptors: a therapeutic perspective. Annu. Rev. Pharmacol. Toxicol. 56, 361–383 (2016).

    Article  CAS  PubMed  Google Scholar 

  117. Matsuta, Y. et al. Melatonin increases bladder capacity via GABAergic system and decreases urine volume in rats. J. Urol. 184, 386–391 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Obayashi, K., Saeki, K. & Kurumatani, N. Association between melatonin secretion and nocturia in elderly individuals: a cross-sectional study of the HEIJO-KYO cohort. J. Urol. 191, 1816–1821 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Leerasiri, P., Pariyaeksut, P., Hengrasmee, P. & Asumpinwong, C. Effectiveness of melatonin for the treatment of nocturia: a randomized controlled trial. Int. Urogynecol. J. 34, 485–492 (2022).

    Article  PubMed  Google Scholar 

  120. Batla, A. et al. Exploratory pilot study of exogenous sustained-release melatonin on nocturia in Parkinson’s disease. Eur. J. Neurol. 28, 1884–1892 (2021).

    Article  PubMed  Google Scholar 

  121. Drake, M. J. et al. Results of a randomized, double blind, placebo controlled, crossover trial of melatonin for treatment of nocturia in adults with multiple sclerosis (MeNiMS). BMC Neurol. 18, 107 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Leng, G., Brown, C. H. & Russell, J. A. Physiological pathways regulating the activity of magnocellular neurosecretory cells. Prog. Neurobiol. 57, 625–655 (1999).

    Article  CAS  PubMed  Google Scholar 

  123. Nielsen, S. et al. Aquaporins in the kidney: from molecules to medicine. Physiol. Rev. 82, 205–244 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. George, C. P. et al. Diurnal variation of plasma vasopressin in man. J. Clin. Endocrinol. Metab. 41, 332–338 (1975).

    Article  CAS  PubMed  Google Scholar 

  125. Ono, D., Honma, K. I. & Honma, S. Roles of neuropeptides, VIP and AVP, in the mammalian central circadian clock. Front. Neurosci. 15, 650154 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Ingram, C. D. et al. Vasopressin neurotransmission and the control of circadian rhythms in the suprachiasmatic nucleus. Prog. Brain Res. 119, 351–364 (1998).

    Article  CAS  PubMed  Google Scholar 

  127. Tousson, E. & Meissl, H. Suprachiasmatic nuclei grafts restore the circadian rhythm in the paraventricular nucleus of the hypothalamus. J. Neurosci. 24, 2983–2988 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Gizowski, C., Trudel, E. & Bourque, C. W. Central and peripheral roles of vasopressin in the circadian defense of body hydration. Best. Pract. Res. Clin. Endocrinol. Metab. 31, 535–546 (2017).

    Article  CAS  PubMed  Google Scholar 

  129. Buijs, R. M. & Kalsbeek, A. Hypothalamic integration of central and peripheral clocks. Nat. Rev. Neurosci. 2, 521–526 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Nakata, M. et al. Circadian clock component BMAL1 in the paraventricular nucleus regulates glucose metabolism. Nutrients 13, 4487 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Bing, M. H. et al. Prevalence and bother of nocturia, and causes of sleep interruption in a Danish population of men and women aged 60–80 years. BJU Int. 98, 599–604 (2006).

    Article  PubMed  Google Scholar 

  132. Obayashi, K., Saeki, K. & Kurumatani, N. Quantitative association between nocturnal voiding frequency and objective sleep quality in the general elderly population: the HEIJO-KYO cohort. Sleep. Med. 16, 577–582 (2015).

    Article  PubMed  Google Scholar 

  133. Kim, S. J. et al. Influence of circadian disruption associated with artificial light at night on micturition patterns in shift workers. Int. Neurourol. J. 23, 258–264 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Cosimo DE, N. et al. Night shift workers refer higher urinary symptoms with an impairment quality of life: a single cohort study. Minerva Urol. Nephrol. 73, 831–835 (2021).

    Google Scholar 

  135. Kamperis, K., Hagstroem, S., Radvanska, E., Rittig, S. & Djurhuus, J. C. Excess diuresis and natriuresis during acute sleep deprivation in healthy adults. Am. J. Physiol. Renal Physiol. 299, F404–F411 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Udo, Y. et al. Sleep duration is an independent factor in nocturia: analysis of bladder diaries. BJU Int. 104, 75–79 (2009).

    Article  PubMed  Google Scholar 

  137. Kalmbach, D. A., Anderson, J. R. & Drake, C. L. The impact of stress on sleep: pathogenic sleep reactivity as a vulnerability to insomnia and circadian disorders. J. Sleep. Res. 27, e12710 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Madhu, C. et al. Nocturia: risk factors and associated comorbidities; findings from the EpiLUTS study. Int. J. Clin. Pract. 69, 1508–1516 (2015).

    Article  CAS  PubMed  Google Scholar 

  139. Deger, M. et al. Risk factors associated with nocturia in patients with obstructive sleep apnea syndrome. Int. J. Clin. Pract. 75, e13724 (2021).

    Article  CAS  PubMed  Google Scholar 

  140. Niimi, A. et al. Sleep apnea and circadian extracellular fluid change as independent factors for nocturnal polyuria. J. Urol. 196, 1183–1189 (2016).

    Article  PubMed  Google Scholar 

  141. Corrado, C. & Fontana, S. Hypoxia and HIF signaling: one axis with divergent effects. Int. J. Mol. Sci. 21, 5611 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Gabryelska, A. et al. Disruption of circadian rhythm genes in obstructive sleep apnea patients-possible mechanisms involved and clinical implication. Int. J. Mol. Sci. 23, 709 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Manella, G. et al. Hypoxia induces a time- and tissue-specific response that elicits intertissue circadian clock misalignment. Proc. Natl Acad. Sci. USA 117, 779–786 (2020).

    Article  CAS  PubMed  Google Scholar 

  144. Ghorbel, M. T., Coulson, J. M. & Murphy, D. Cross-talk between hypoxic and circadian pathways: cooperative roles for hypoxia-inducible factor 1α and CLOCK in transcriptional activation of the vasopressin gene. Mol. Cell Neurosci. 22, 396–404 (2003).

    Article  CAS  PubMed  Google Scholar 

  145. Wuerzner, G., Firsov, D. & Bonny, O. Circadian glomerular function: from physiology to molecular and therapeutical aspects. Nephrol. Dial. Transplant. 29, 1475–1480 (2014).

    Article  PubMed  Google Scholar 

  146. Johnston, J. G. & Pollock, D. M. Circadian regulation of renal function. Free Radic. Biol. Med. 119, 93–107 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Pollak, M. R., Quaggin, S. E., Hoenig, M. P. & Dworkin, L. D. The glomerulus: the sphere of influence. Clin. J. Am. Soc. Nephrol. 9, 1461–1469 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Mills, J. N. Human circadian rhythms. Physiol. Rev. 46, 128–171 (1966).

    Article  CAS  PubMed  Google Scholar 

  149. Rossier, B. C., Baker, M. E. & Studer, R. A. Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited. Physiol. Rev. 95, 297–340 (2015).

    Article  PubMed  Google Scholar 

  150. Hurwitz, S., Cohen, R. J. & Williams, G. H. Diurnal variation of aldosterone and plasma renin activity: timing relation to melatonin and cortisol and consistency after prolonged bed rest. J. Appl. Physiol. 96, 1406–1414 (2004).

    Article  CAS  PubMed  Google Scholar 

  151. Firsov, D. & Bonny, O. Circadian regulation of renal function. Kidney Int. 78, 640–645 (2010).

    Article  PubMed  Google Scholar 

  152. Mills, J. N. & Stanbury, S. W. Persistent 24-hour renal excretory rhythm on a 12-hour cycle of activity. J. Physiol. 117, 22–37 (1952).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Mills, J. N. Diurnal rhythm in urine flow. J. Physiol. 113, 528–536 (1951).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Mills, J. N. & Stanbury, S. W. Intrinsic diurnal rhythm in urinary electrolyte output. J. Physiol. 115, 18p–19p (1951).

    CAS  PubMed  Google Scholar 

  155. Ede, M. C., Faulkner, M. H. & Tredre, B. E. An intrinsic rhythm of urinary calcium excretion and the specific effect of bedrest on the excretory pattern. Clin. Sci. 42, 433–445 (1972).

    Article  CAS  PubMed  Google Scholar 

  156. Moore-Ede, M. C. & Herd, J. A. Renal electrolyte circadian rhythms: independence from feeding and activity patterns. Am. J. Physiol. 232, F128–F135 (1977).

    CAS  PubMed  Google Scholar 

  157. Firsov, D. & Bonny, O. Circadian rhythms and the kidney. Nat. Rev. Nephrol. 14, 626–635 (2018).

    Article  CAS  PubMed  Google Scholar 

  158. Stow, L. R. & Gumz, M. L. The circadian clock in the kidney. J. Am. Soc. Nephrol. 22, 598–604 (2011).

    Article  CAS  PubMed  Google Scholar 

  159. Zuber, A. M. et al. Molecular clock is involved in predictive circadian adjustment of renal function. Proc. Natl Acad. Sci. USA 106, 16523–16528 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Solocinski, K. & Gumz, M. L. The circadian clock in the regulation of renal rhythms. J. Biol. Rhythm. 30, 470–486 (2015).

    Article  CAS  Google Scholar 

  161. Doi, M. et al. Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6. Nat. Med. 16, 67–74 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. Nikolaeva, S. et al. The circadian clock modulates renal sodium handling. J. Am. Soc. Nephrol. 23, 1019–1026 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Ge, Y. et al. Endogenously produced 20-HETE modulates myogenic and TGF response in microperfused afferent arterioles. Prostaglandins Other Lipid Mediat. 102–103, 42–48 (2013).

    Article  PubMed  Google Scholar 

  164. Tokonami, N. et al. Local renal circadian clocks control fluid-electrolyte homeostasis and BP. J. Am. Soc. Nephrol. 25, 1430–1439 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Ansermet, C. et al. The intrinsic circadian clock in podocytes controls glomerular filtration rate. Sci. Rep. 9, 16089 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Nikolaeva, S. et al. Nephron-specific deletion of circadian clock gene Bmal1 alters the plasma and renal metabolome and impairs drug disposition. J. Am. Soc. Nephrol. 27, 2997–3004 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Soundararajan, R., Pearce, D. & Ziera, T. The role of the ENaC-regulatory complex in aldosterone-mediated sodium transport. Mol. Cell Endocrinol. 350, 242–247 (2012).

    Article  CAS  PubMed  Google Scholar 

  168. Gumz, M. L. Molecular basis of circadian rhythmicity in renal physiology and pathophysiology. Exp. Physiol. 101, 1025–1029 (2016).

    Article  CAS  PubMed  Google Scholar 

  169. Gumz, M. L. et al. The circadian clock protein Period 1 regulates expression of the renal epithelial sodium channel in mice. J. Clin. Invest. 119, 2423–2434 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Richards, J. et al. A role for the circadian clock protein Per1 in the regulation of the NaCl co-transporter (NCC) and the with-no-lysine kinase (WNK) cascade in mouse distal convoluted tubule cells. J. Biol. Chem. 289, 11791–11806 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Solocinski, K. et al. Transcriptional regulation of NHE3 and SGLT1 by the circadian clock protein Per1 in proximal tubule cells. Am. J. Physiol. Renal Physiol. 309, F933–F942 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Stow, L. R. et al. The circadian protein period 1 contributes to blood pressure control and coordinately regulates renal sodium transport genes. Hypertension 59, 1151–1156 (2012).

    Article  CAS  PubMed  Google Scholar 

  173. Richards, J. et al. Tissue-specific and time-dependent regulation of the endothelin axis by the circadian clock protein Per1. Life Sci. 118, 255–262 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Kohan, D. E., Inscho, E. W., Wesson, D. & Pollock, D. M. Physiology of endothelin and the kidney. Compr. Physiol. 1, 883–919 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Douma, L. G. et al. Kidney-specific KO of the circadian clock protein PER1 alters renal Na+ handling, aldosterone levels, and kidney/adrenal gene expression. Am. J. Physiol. Renal Physiol. 322, F449–F459 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Miller, M. Nocturnal polyuria in older people: pathophysiology and clinical implications. J. Am. Geriatr. Soc. 48, 1321–1329 (2000).

    Article  CAS  PubMed  Google Scholar 

  177. Schmitt, E. E., Johnson, E. C., Yusifova, M. & Bruns, D. R. The renal molecular clock: broken by aging and restored by exercise. Am. J. Physiol. Renal Physiol. 317, F1087–F1093 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Cugini, P. et al. Effect of aging on circadian rhythm of atrial natriuretic peptide, plasma renin activity, and plasma aldosterone. J. Gerontol. 47, B214–B219 (1992).

    Article  CAS  PubMed  Google Scholar 

  179. Kirkland, J. L., Lye, M., Levy, D. W. & Banerjee, A. K. Patterns of urine flow and electrolyte excretion in healthy elderly people. Br. Med. J. 287, 1665–1667 (1983).

    Article  CAS  Google Scholar 

  180. Wolff, C. A. et al. Defining the age-dependent and tissue-specific circadian transcriptome in male mice. Cell Rep. 42, 111982 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Moon, D. G. et al. Antidiuretic hormone in elderly male patients with severe nocturia: a circadian study. BJU Int. 94, 571–575 (2004).

    Article  CAS  PubMed  Google Scholar 

  182. Asplund, R. Diuresis pattern, plasma vasopressin and blood pressure in healthy elderly persons with nocturia and nocturnal polyuria. Neth. J. Med. 60, 276–280 (2002).

    CAS  PubMed  Google Scholar 

  183. Tamma, G., Goswami, N., Reichmuth, J., De Santo, N. G. & Valenti, G. Aquaporins, vasopressin, and aging: current perspectives. Endocrinology 156, 777–788 (2015).

    Article  CAS  PubMed  Google Scholar 

  184. Carter, P. G., Cannon, A., McConnell, A. A. & Abrams, P. Role of atrial natriuretic peptide in nocturnal polyuria in elderly males. Eur. Urol. 36, 213–220 (1999).

    Article  CAS  PubMed  Google Scholar 

  185. Matthiesen, T. B., Rittig, S., Norgaard, J. P., Pedersen, E. B. & Djurhuus, J. C. Nocturnal polyuria and natriuresis in male patients with nocturia and lower urinary tract symptoms. J. Urol. 156, 1292–1299 (1996).

    Article  CAS  PubMed  Google Scholar 

  186. Johnson, T. M. II, Miller, M., Pillion, D. J. & Ouslander, J. G. Arginine vasopressin and nocturnal polyuria in older adults with frequent nighttime voiding. J. Urol. 170, 480–484 (2003).

    Article  CAS  PubMed  Google Scholar 

  187. Asplund, R., Sundberg, B. & Bengtsson, P. Oral desmopressin for nocturnal polyuria in elderly subjects: a double-blind, placebo-controlled randomized exploratory study. BJU Int. 83, 591–595 (1999).

    Article  CAS  PubMed  Google Scholar 

  188. Mohandas, R., Douma, L. G., Scindia, Y. & Gumz, M. L. Circadian rhythms and renal pathophysiology. J. Clin. Invest. 132, e148277 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Graugaard-Jensen, C., Rittig, S. & Djurhuus, J. C. Nocturia and circadian blood pressure profile in healthy elderly male volunteers. J. Urol. 176, 1034–1039 (2006).

    Article  PubMed  Google Scholar 

  190. Weiss, J. P., Monaghan, T. F., Epstein, M. R. & Lazar, J. M. Future considerations in nocturia and nocturnal polyuria. Urology 133S, 34–42 (2019).

    Article  PubMed  Google Scholar 

  191. Fujii, T. et al. Circadian rhythm of natriuresis is disturbed in nondipper type of essential hypertension. Am. J. Kidney Dis. 33, 29–35 (1999).

    Article  CAS  PubMed  Google Scholar 

  192. Sachdeva, A. & Weder, A. B. Nocturnal sodium excretion, blood pressure dipping, and sodium sensitivity. Hypertension 48, 527–533 (2006).

    Article  CAS  PubMed  Google Scholar 

  193. Matsuo, T., Miyata, Y. & Sakai, H. Effect of salt intake reduction on nocturia in patients with excessive salt intake. Neurourol. Urodyn. 38, 927–933 (2019).

    Article  CAS  PubMed  Google Scholar 

  194. Okumura, Y. et al. Dietary sodium restriction reduces nocturnal urine volume and nocturnal polyuria index in renal allograft recipients with nocturnal polyuria. Urology 106, 60–64 (2017).

    Article  PubMed  Google Scholar 

  195. Nakamura, S. et al. Circadian changes in urine volume and frequency in elderly men. J. Urol. 156, 1275–1279 (1996).

    Article  CAS  PubMed  Google Scholar 

  196. Summers, S. J. et al. Male voiding behavior: insight from 19,824 at-home uroflow profiles. J. Urol. 205, 1126–1132 (2021).

    Article  PubMed  Google Scholar 

  197. Kono, J. et al. Urothelium-specific deletion of connexin43 in the mouse urinary bladder alters distension-induced ATP release and voiding behavior. Int. J. Mol. Sci. 22, 1594 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Herrera, G. M. & Meredith, A. L. Diurnal variation in urodynamics of rat. PLoS ONE 5, e12298 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Negoro, H. et al. Development of diurnal micturition pattern in mice after weaning. J. Urol. 189, 740–746 (2013).

    Article  PubMed  Google Scholar 

  200. Langdale, C. L., Degoski, D., Milliken, P. H. & Grill, W. M. Voiding behavior in awake unrestrained untethered spontaneously hypertensive and Wistar control rats. Am. J. Physiol. Renal Physiol. 321, F195–F206 (2021).

    Article  CAS  PubMed  Google Scholar 

  201. Ihara, T. et al. Intermittent restraint stress induces circadian misalignment in the mouse bladder, leading to nocturia. Sci. Rep. 9, 10069 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Kimura, Y. et al. The circadian rhythm of bladder clock genes in the spontaneously hypersensitive rat. PLoS ONE 14, e0220381 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Wu, C. et al. Local receptors as novel regulators for peripheral clock expression. FASEB J. 28, 4610–4616 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Christie, S. & Zagorodnyuk, V. Time-of-day dependent changes in guinea pig bladder afferent mechano-sensitivity. Sci. Rep. 11, 19283 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Witjes, W. P., Wijkstra, H., Debruyne, F. M. & de la Rosette, J. J. Quantitative assessment of uroflow: is there a circadian rhythm? Urology 50, 221–228 (1997).

    Article  CAS  PubMed  Google Scholar 

  206. Hiramatsu, I. et al. Maximum flow rate is lowest in the early morning in hospitalized men with nocturia evaluated over 24 hours by toilet uroflowmetry. Urology 166, 196–201 (2022).

    Article  PubMed  Google Scholar 

  207. Negoro, H. et al. Diurnal differences in urine flow in healthy young men in a light-controlled environment: a randomized crossover design. J. Physiol. Anthropol. 42, 27 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Huppertz, N. D., Kirschner-Hermanns, R., Tolba, R. H. & Grosse, J. O. Telemetric monitoring of bladder function in female Göttingen minipigs. BJU Int. 116, 823–832 (2015).

    Article  PubMed  Google Scholar 

  209. White, R. S. et al. Evaluation of mouse urinary bladder smooth muscle for diurnal differences in contractile properties. Front. Pharmacol. 5, 293 (2014).

    PubMed  Google Scholar 

  210. Negoro, H., Kanematsu, A., Yoshimura, K. & Ogawa, O. Chronobiology of micturition: putative role of the circadian clock. J. Urol. 190, 843–849 (2013).

    Article  PubMed  Google Scholar 

  211. Ihara, T. et al. The Circadian expression of Piezo1, TRPV4, Connexin26, and VNUT, associated with the expression levels of the clock genes in mouse primary cultured urothelial cells. Neurourol. Urodyn. 37, 942–951 (2018).

    Article  CAS  PubMed  Google Scholar 

  212. Ihara, T. et al. The oscillation of intracellular Ca2+ influx associated with the circadian expression of Piezo1 and TRPV4 in the bladder urothelium. Sci. Rep. 8, 5699 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Ihara, T. et al. The time-dependent variation of ATP release in mouse primary-cultured urothelial cells is regulated by the clock gene. Neurourol. Urodyn. 37, 2535–2543 (2018).

    Article  CAS  PubMed  Google Scholar 

  214. Ihara, T. et al. Clock genes regulate the circadian expression of Piezo1, TRPV4, Connexin26, and VNUT in an ex vivo mouse bladder mucosa. PLoS ONE 12, e0168234 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Birder, L. A. & Van Kerrebroeck, P. E. V. Pathophysiological mechanisms of nocturia and nocturnal polyuria: the contribution of cellular function, the urinary bladder urothelium, and circadian rhythm. Urology 133S, 14–23 (2019).

    Article  PubMed  Google Scholar 

  216. Dalghi, M. G., Montalbetti, N., Carattino, M. D. & Apodaca, G. The urothelium: life in a liquid environment. Physiol. Rev. 100, 1621–1705 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Ali, A. A. H., Avakian, G. A. & Gall, C. V. the role of purinergic receptors in the circadian system. Int. J. Mol. Sci. 21, 3423 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Thoma, C. Urinary incontinence: the bladder sets its own clock. Nat. Rev. Urol. 11, 544 (2014).

    Article  PubMed  Google Scholar 

  219. Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y. & Menaker, M. Entrainment of the circadian clock in the liver by feeding. Science 291, 490–493 (2001).

    Article  CAS  PubMed  Google Scholar 

  220. Ikeda, Y. et al. Glucagon and/or IGF-1 production regulates resetting of the liver circadian clock in response to a protein or amino acid-only diet. EBioMedicine 28, 210–224 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  221. Chihara, I. et al. Glucocorticoids coordinate the bladder peripheral clock and diurnal micturition pattern in mice. Commun. Biol. 6, 81 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  222. Noh, J. Y. et al. Presence of multiple peripheral circadian oscillators in the tissues controlling voiding function in mice. Exp. Mol. Med. 46, e81 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Ihara, T. et al. The Clock mutant mouse is a novel experimental model for nocturia and nocturnal polyuria. Neurourol. Urodyn. 36, 1034–1038 (2017).

    Article  CAS  PubMed  Google Scholar 

  224. Belancio, V. P., Blask, D. E., Deininger, P., Hill, S. M. & Jazwinski, S. M. The aging clock and circadian control of metabolism and genome stability. Front. Genet. 5, 455 (2014).

    PubMed  Google Scholar 

  225. Silva-Ramos, M. et al. Urinary ATP may be a dynamic biomarker of detrusor overactivity in women with overactive bladder syndrome. PLoS ONE 8, e64696 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Homma, Y., Yamaguchi, O. & Hayashi, K. An epidemiological survey of overactive bladder symptoms in Japan. BJU Int. 96, 1314–1318 (2005).

    Article  PubMed  Google Scholar 

  227. Goessaert, A. S., Krott, L., Walle, J. V. & Everaert, K. Exploring nocturia: gender, age, and causes. Neurourol. Urodyn. 34, 561–565 (2015).

    Article  CAS  PubMed  Google Scholar 

  228. Presicce, F. et al. Variations of nighttime and daytime bladder capacity in patients with nocturia: implication for diagnosis and treatment. J. Urol. 201, 962–966 (2019).

    Article  PubMed  Google Scholar 

  229. Iwamoto, T. et al. Reduced salt intake partially restores the circadian rhythm of bladder clock genes in Dahl salt-sensitive rats. Life Sci. 306, 120842 (2022).

    Article  CAS  PubMed  Google Scholar 

  230. Griffett, K. & Burris, T. P. The mammalian clock and chronopharmacology. Bioorg. Med. Chem. Lett. 23, 1929–1934 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Ruan, W., Yuan, X. & Eltzschig, H. K. Circadian rhythm as a therapeutic target. Nat. Rev. Drug. Discov. 20, 287–307 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. LeGates, T. A., Fernandez, D. C. & Hattar, S. Light as a central modulator of circadian rhythms, sleep and affect. Nat. Rev. Neurosci. 15, 443–454 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Gooley, J. J. Treatment of circadian rhythm sleep disorders with light. Ann. Acad. Med. Singap. 37, 669–676 (2008).

    Article  PubMed  Google Scholar 

  234. Gehlbach, B. K. et al. The effects of timed light exposure in critically Ill patients: a randomized controlled pilot clinical trial. Am. J. Respir. Crit. Care Med. 198, 275–278 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Ono, H., Taguchi, T., Kido, Y., Fujino, Y. & Doki, Y. The usefulness of bright light therapy for patients after oesophagectomy. Intensive Crit. Care Nurs. 27, 158–166 (2011).

    Article  PubMed  Google Scholar 

  236. Taguchi, T., Yano, M. & Kido, Y. Influence of bright light therapy on postoperative patients: a pilot study. Intensive Crit. Care Nurs. 23, 289–297 (2007).

    Article  PubMed  Google Scholar 

  237. Yang, J. et al. Bright light therapy as an adjunctive treatment with risperidone in patients with delirium: a randomized, open, parallel group study. Gen. Hosp. Psychiatry 34, 546–551 (2012).

    Article  CAS  PubMed  Google Scholar 

  238. Challet, E. The circadian regulation of food intake. Nat. Rev. Endocrinol. 15, 393–405 (2019).

    Article  PubMed  Google Scholar 

  239. Sutton, E. F. et al. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. Cell Metab. 27, 1212–1221.e3 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Chaix, A., Zarrinpar, A., Miu, P. & Panda, S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell Metab. 20, 991–1005 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Mrosovsky, N. & Salmon, P. A. A behavioural method for accelerating re-entrainment of rhythms to new light-dark cycles. Nature 330, 372–373 (1987).

    Article  CAS  PubMed  Google Scholar 

  242. Reid, K. J. et al. Aerobic exercise improves self-reported sleep and quality of life in older adults with insomnia. Sleep. Med. 11, 934–940 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  243. Buxton, O. M., Lee, C. W., L’Hermite-Baleriaux, M., Turek, F. W. & Van Cauter, E. Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R714–R724 (2003).

    Article  CAS  PubMed  Google Scholar 

  244. Meyer, N., Harvey, A. G., Lockley, S. W. & Dijk, D. J. Circadian rhythms and disorders of the timing of sleep. Lancet 400, 1061–1078 (2022).

    Article  PubMed  Google Scholar 

  245. Panda, S. The arrival of circadian medicine. Nat. Rev. Endocrinol. 15, 67–69 (2019).

    Article  PubMed  Google Scholar 

  246. Yu, F. et al. Recent advances in circadian-regulated pharmacokinetics and its implications for chronotherapy. Biochem. Pharmacol. 203, 115185 (2022).

    Article  CAS  PubMed  Google Scholar 

  247. Burgess, H. J., Revell, V. L. & Eastman, C. I. A three pulse phase response curve to three milligrams of melatonin in humans. J. Physiol. 586, 639–647 (2008).

    Article  CAS  PubMed  Google Scholar 

  248. Zhao, M., Zhao, H., Deng, J., Guo, L. & Wu, B. Role of the CLOCK protein in liver detoxification. Br. J. Pharmacol. 176, 4639–4652 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Winter, C. et al. Chrono-pharmacological targeting of the CCL2-CCR2 axis ameliorates atherosclerosis. Cell Metab. 28, 175–182.e5 (2018).

    Article  CAS  PubMed  Google Scholar 

  250. Levi, F. & Schibler, U. Circadian rhythms: mechanisms and therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 47, 593–628 (2007).

    Article  CAS  PubMed  Google Scholar 

  251. Humphries, P. S. et al. Carbazole-containing amides and ureas: discovery of cryptochrome modulators as antihyperglycemic agents. Bioorg. Med. Chem. Lett. 28, 293–297 (2018).

    Article  CAS  PubMed  Google Scholar 

  252. Miller, S. et al. Isoform-selective regulation of mammalian cryptochromes. Nat. Chem. Biol. 16, 676–685 (2020).

    Article  CAS  PubMed  Google Scholar 

  253. Hirota, T. et al. Identification of small molecule activators of cryptochrome. Science 337, 1094–1097 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Dong, Z. et al. Targeting glioblastoma stem cells through disruption of the circadian clock. Cancer Discov. 9, 1556–1573 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Solt, L. A. et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485, 62–68 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Banerjee, S. et al. Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour. Nat. Commun. 5, 5759 (2014).

    Article  CAS  PubMed  Google Scholar 

  257. He, B. et al. The small molecule nobiletin targets the molecular oscillator to enhance circadian rhythms and protect against metabolic syndrome. Cell Metab. 23, 610–621 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. EE, M., AC, B. & MW, H. Citrus flavonoids as regulators of lipoprotein metabolism and atherosclerosis. Annu. Rev. Nutr. 36, 275–299 (2016).

    Article  Google Scholar 

  259. Shinozaki, A. et al. Potent effects of flavonoid nobiletin on amplitude, period, and phase of the circadian clock rhythm in PER2::LUCIFERASE mouse embryonic fibroblasts. PLoS ONE 12, e0170904 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  260. Ihara, T. et al. Different effects of GsMTx4 on nocturia associated with the circadian clock and Piezo1 expression in mice. Life Sci. 278, 119555 (2021).

    Article  CAS  PubMed  Google Scholar 

  261. Kira, S. et al. Urinary metabolites identified using metabolomic analysis as potential biomarkers of nocturia in elderly men. World J. Urol. 38, 2563–2569 (2020).

    Article  CAS  PubMed  Google Scholar 

  262. Ihara, T. et al. Effects of fatty acid metabolites on nocturia. Sci. Rep. 12, 3050 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Ihara, T. et al. G protein-coupled receptor 55 activated by palmitoylethanolamide is associated with the development of nocturia associated with circadian rhythm disorders. Life Sci. 332, 122072 (2023).

    Article  CAS  PubMed  Google Scholar 

  264. Ito, H. et al. Effectiveness and safety of a mixture of nobiletin and tangeretin in nocturia patients: a randomized, placebo-controlled, double-blind, crossover study. J. Clin. Med. 12, 2757 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Pauwaert, K. et al. Does hormonal therapy affect the bladder or the kidney in postmenopausal women with and without nocturnal polyuria: results of a pilot trial? Maturitas 160, 61–67 (2022).

    Article  CAS  PubMed  Google Scholar 

  266. Simonneaux, V. et al. Daily rhythm and regulation of clock gene expression in the rat pineal gland. Brain Res. Brain Res. Mol. Brain Res. 120, 164–172 (2004).

    Article  CAS  PubMed  Google Scholar 

  267. von Gall, C. et al. Clock gene protein mPER1 is rhythmically synthesized and under cAMP control in the mouse pineal organ. J. Neuroendocrinol. 13, 313–316 (2001).

    Article  Google Scholar 

  268. Ono, D., Honma, S. & Honma, K. Differential roles of AVP and VIP signaling in the postnatal changes of neural networks for coherent circadian rhythms in the SCN. Sci. Adv. 2, e1600960 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

Q.-X.S., S.O.S., H.N., H.-H.J. and R.J. researched data for the article. All authors contributed substantially to discussion of the content. All authors wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Margot S. Damaser.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Urology thanks Irina Verbakel and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, QX., Suadicani, S.O., Negoro, H. et al. Disruption of circadian rhythm as a potential pathogenesis of nocturia. Nat Rev Urol 22, 276–293 (2025). https://doi.org/10.1038/s41585-024-00961-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41585-024-00961-0

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing