Circadian Clock Genes in Diabetic Kidney Disease (DKD)

  • Olanrewaju A. Olaoye
  • Sarah H. Masten
  • Rajesh Mohandas
  • Michelle L. GumzEmail author
Microvascular Complications—Nephropathy (M Afkarian and B Roshanravan, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Microvascular Complications—Nephropathy


Purpose of Review

The purpose of this review is to provide a brief summary about the current state of knowledge regarding the circadian rhythm in the regulation of normal renal function.

Recent Findings

There is a lack of information regarding how the circadian clock mechanisms may contribute to the development of diabetic kidney disease. We discuss recent findings regarding mechanisms that are established in diabetic kidney disease and are known to be linked to the circadian clock as possible connections between these two areas.


Here, we hypothesize various mechanisms that may provide a link between the clock mechanism and kidney disease in diabetes based on available data from humans and rodent models.


Circadian rhythm Renal function HIF Shift work BMAL1 


Compliance With Ethical Standards

Conflict of Interest

Olanrewaju A. Olaoye, Sarah H. Masten, Rajesh Mohandas, and Michelle L. Gumz declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol. 2010;72:517–49. Scholar
  2. 2.
    Atger F, Mauvoisin D, Weger B, Gobet C, Gachon F. Regulation of mammalian physiology by interconnected circadian and feeding rhythms. Front Endocrinol. 2017;8:42. Scholar
  3. 3.
    Meszaros K, Pruess L, Szabo AJ, Gondan M, Ritz E, Schaefer F. Development of the circadian clockwork in the kidney. Kidney Int. 2014;86(5):915–22. Scholar
  4. 4.
    Mazzoccoli G, Francavilla M, Giuliani F, Aucella F, Vinciguerra M, Pazienza V, et al. Clock gene expression in mouse kidney and testis: analysis of periodical and dynamical patterns. J Biol Regul Homeost Agents. 2012;26(2):303–11.PubMedGoogle Scholar
  5. 5.
    Wu T, Ni Y, Dong Y, Xu J, Song X, Kato H, et al. Regulation of circadian gene expression in the kidney by light and food cues in rats. Am J Physiol Regul Integr Comp Physiol. 2010;298(3):R635–41. Scholar
  6. 6.
    Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci U S A. 2014;111(45):16219–24. Scholar
  7. 7.
    Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell. 2002;109(3):307–20.CrossRefGoogle Scholar
  8. 8.
    Storch KF, Lipan O, Leykin I, Viswanathan N, Davis FC, Wong WH, et al. Extensive and divergent circadian gene expression in liver and heart. Nature. 2002;417(6884):78–83. Scholar
  9. 9.
    Koopman MG, Koomen GC, Krediet RT, de Moor EA, Hoek FJ, Arisz L. Circadian rhythm of glomerular filtration rate in normal individuals. Clin Sci (London, England: 1979). 1989;77(1):105–11.CrossRefGoogle Scholar
  10. 10.
    Koopman MG, Krediet RT, Koomen GC, Strackee J, Arisz L. Circadian rhythm of proteinuria: consequences of the use of urinary protein:creatinine ratios. Nephrol Dial Transplant. 1989;4(1):9–14.PubMedGoogle Scholar
  11. 11.
    Voogel AJ, Koopman MG, Hart AA, van Montfrans GA, Arisz L. Circadian rhythms in systemic hemodynamics and renal function in healthy subjects and patients with nephrotic syndrome. Kidney Int. 2001;59(5):1873–80. Scholar
  12. 12.
    Firsov D, Bonny O. Circadian rhythms and the kidney. Nat Rev Nephrol. 2018;14(10):626–35. Scholar
  13. 13.
    Solocinski K, Holzworth M, Wen X, Cheng KY, Lynch IJ, Cain BD, et al. Desoxycorticosterone pivalate-salt treatment leads to non-dipping hypertension in Per1 knockout mice. Acta Physiol (Oxford, England). 2017;220(1):72–82. Scholar
  14. 14.
    Douma LG, Holzworth MR, Solocinski K, Masten SH, Miller AH, Cheng KY, et al. Renal Na-handling defect associated with PER1-dependent nondipping hypertension in male mice. Am J Physiol Ren Physiol. 2018;314(6):F1138–44. Scholar
  15. 15.
    Solocinski K, Richards J, All S, Cheng KY, Khundmiri SJ, Gumz ML. Transcriptional regulation of NHE3 and SGLT1 by the circadian clock protein Per1 in proximal tubule cells. Am J Physiol Ren Physiol. 2015;309(11):F933–42. Scholar
  16. 16.
    Stow LR, Richards J, Cheng KY, Lynch IJ, Jeffers LA, Greenlee MM, et al. The circadian protein period 1 contributes to blood pressure control and coordinately regulates renal sodium transport genes. Hypertension (Dallas, Tex : 1979). 2012;59(6):1151–6. Scholar
  17. 17.
    Richards J, Ko B, All S, Cheng KY, Hoover RS, Gumz ML. 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. 2014;289(17):11791–806. Scholar
  18. 18.
    Tokonami N, Mordasini D, Pradervand S, Centeno G, Jouffe C, Maillard M, et al. Local renal circadian clocks control fluid-electrolyte homeostasis and BP. J Am Soc Nephrol. 2014;25(7):1430–9. Scholar
  19. 19.
    Hara M, Minami Y, Ohashi M, Tsuchiya Y, Kusaba T, Tamagaki K, et al. Robust circadian clock oscillation and osmotic rhythms in inner medulla reflecting cortico-medullary osmotic gradient rhythm in rodent kidney. Sci Rep. 2017;7(1):7306. Scholar
  20. 20.
    Salhi A, Centeno G, Firsov D, Crambert G. Circadian expression of H,K-ATPase type 2 contributes to the stability of plasma K(+) levels. FASEB J. 2012;26(7):2859–67. Scholar
  21. 21.
    Pouly D, Chenaux S, Martin V, Babis M, Koch R, Nagoshi E, et al. USP2-45 is a circadian clock output effector regulating calcium absorption at the post-translational level. PLoS One. 2016;11(1):e0145155. Scholar
  22. 22.
    Zuber AM, Centeno G, Pradervand S, Nikolaeva S, Maquelin L, Cardinaux L, et al. Molecular clock is involved in predictive circadian adjustment of renal function. Proc Natl Acad Sci U S A. 2009;106(38):16523–8. Scholar
  23. 23.
    Pradervand S, Zuber Mercier A, Centeno G, Bonny O, Firsov D. A comprehensive analysis of gene expression profiles in distal parts of the mouse renal tubule. Pflugers Arch - Eur J Physiol. 2010;460(6):925–52. Scholar
  24. 24.
    Prudente S, Di Paola R, Copetti M, Lucchesi D, Lamacchia O, Pezzilli S, et al. The rs12917707 polymorphism at the UMOD locus and glomerular filtration rate in individuals with type 2 diabetes: evidence of heterogeneity across two different European populations. Nephrol Dial Transplant. 2017;32(10):1718–22. Scholar
  25. 25.
    Ahluwalia TS, Lindholm E, Groop L, Melander O. Uromodulin gene variant is associated with type 2 diabetic nephropathy. J Hypertens. 2011;29(9):1731–4. Scholar
  26. 26.
    Bleyer AJ, Kmoch S. Tamm Horsfall glycoprotein and uromodulin: it is all about the tubules! Clin J Am Soc Nephrol. 2016;11(1):6–8. Scholar
  27. 27.
    Lynn KL, Shenkin A, Marshall RD. Factors affecting excretion of human urinary Tamm-Horsfall glycoprotein. Clin Sci (Lond). 1982;62(1):21–6.CrossRefGoogle Scholar
  28. 28.
    Nikolaeva S, Ansermet C, Centeno G, Pradervand S, Bize V, Mordasini D, et al. Nephron-specific deletion of circadian clock gene Bmal1 alters the plasma and renal Metabolome and impairs drug disposition. J Am Soc Nephrol. 2016;27(10):2997–3004. Scholar
  29. 29.
    Quigley R, Baum M, Reddy KM, Griener JC, Falck JR. Effects of 20-HETE and 19(S)-HETE on rabbit proximal straight tubule volume transport. Am J Physiol Ren Physiol. 2000;278(6):F949–53. Scholar
  30. 30.
    Rossier BC, Baker ME, Studer RA. Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited. Physiol Rev. 2015;95(1):297–340. Scholar
  31. 31.
    Hurwitz S, Cohen RJ, Williams GH. Diurnal variation of aldosterone and plasma renin activity: timing relation to melatonin and cortisol and consistency after prolonged bed rest. J Appl Physiol (Bethesda, Md: 1985). 2004;96(4):1406–14. Scholar
  32. 32.
    Doi M, Takahashi Y, Komatsu R, Yamazaki F, Yamada H, Haraguchi S, et al. Salt-sensitive hypertension in circadian clock-deficient cry-null mice involves dysregulated adrenal Hsd3b6. Nat Med. 2010;16(1):67–74. Scholar
  33. 33.
    Richards J, Cheng KY, All S, Skopis G, Jeffers L, Lynch IJ, et al. A role for the circadian clock protein Per1 in the regulation of aldosterone levels and renal Na+ retention. Am J Physiol Ren Physiol. 2013;305(12):F1697–704. Scholar
  34. 34.
    Gumz ML, Stow LR, Lynch IJ, Greenlee MM, Rudin A, Cain BD, et al. The circadian clock protein period 1 regulates expression of the renal epithelial sodium channel in mice. J Clin Invest. 2009;119(8):2423–34. Scholar
  35. 35.
    Gumz ML, Cheng KY, Lynch IJ, Stow LR, Greenlee MM, Cain BD, et al. Regulation of alphaENaC expression by the circadian clock protein period 1 in mpkCCD(c14) cells. Biochim Biophys Acta. 2010;1799(9):622–9. Scholar
  36. 36.
    Richards J, Jeffers LA, All SC, Cheng KY, Gumz ML. Role of Per1 and the mineralocorticoid receptor in the coordinate regulation of alphaENaC in renal cortical collecting duct cells. Front Physiol. 2013;4:253. Scholar
  37. 37.
    Richards J, Welch AK, Barilovits SJ, All S, Cheng KY, Wingo CS, et al. Tissue-specific and time-dependent regulation of the endothelin axis by the circadian clock protein Per1. Life Sci. 2014;118(2):255–62. Scholar
  38. 38.
    Castelo-Szekely V, Arpat AB, Janich P, Gatfield D. Translational contributions to tissue specificity in rhythmic and constitutive gene expression. Genome Biol. 2017;18(1):116. Scholar
  39. 39.
    Jouffe C, Cretenet G, Symul L, Martin E, Atger F, Naef F, et al. The circadian clock coordinates ribosome biogenesis. PLoS Biol. 2013;11(1):e1001455. Scholar
  40. 40.
    Atger F, Gobet C, Marquis J, Martin E, Wang J, Weger B, et al. Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver. Proc Natl Acad Sci U S A. 2015;112(47):E6579–88. Scholar
  41. 41.
    Susa K, Sohara E, Isobe K, Chiga M, Rai T, Sasaki S, et al. WNK-OSR1/SPAK-NCC signal cascade has circadian rhythm dependent on aldosterone. Biochem Biophys Res Commun. 2012;427(4):743–7. Scholar
  42. 42.
    Ivy JR, Oosthuyzen W, Peltz TS, Howarth AR, Hunter RW, Dhaun N, et al. Glucocorticoids induce nondipping blood pressure by activating the thiazide-sensitive cotransporter. Hypertension. 2016;67(5):1029–37. Scholar
  43. 43.
    •• Robles MS, Humphrey SJ, Mann M. Phosphorylation is a central mechanism for circadian control of metabolism and physiology. Cell Metab. 2017;25(1):118–27. The results of this important work provide clear evidence linking rhythms in tissue oxygenation, including the kidney, to the circadian clock mechanism. CrossRefPubMedGoogle Scholar
  44. 44.
    Adamovich Y, Ladeuix B, Golik M, Koeners MP, Asher G. Rhythmic oxygen levels reset circadian clocks through HIF1alpha. Cell Metab. 2017;25(1):93–101. Scholar
  45. 45.
    Walton ZE, Patel CH, Brooks RC, Yu Y, Ibrahim-Hashim A, Riddle M, et al. Acid suspends the circadian clock in hypoxia through inhibition of mTOR. Cell. 2018;174(1):72–87.e32. Scholar
  46. 46.
    Peschke E, Bahr I, Muhlbauer E. Experimental and clinical aspects of melatonin and clock genes in diabetes. J Pineal Res. 2015;59(1):1–23. Scholar
  47. 47.
    Stenvers DJ, Scheer F, Schrauwen P, la Fleur SE, Kalsbeek A. Circadian clocks and insulin resistance. Nat Rev Endocrinol. 2018;15:75–89. Scholar
  48. 48.
    Soltesova D, Monosikova J, Koysova L, Vesela A, Mravec B, Herichova I. Effect of streptozotocin-induced diabetes on clock gene expression in tissues inside and outside the blood-brain barrier in rat. Exp Clin Endocrinol Diabetes. 2013;121(8):466–74. CrossRefPubMedGoogle Scholar
  49. 49.
    Angelousi A, Kassi E, Nasiri-Ansari N, Weickert MO, Randeva H, Kaltsas G. Clock genes alterations and endocrine disorders. Eur J Clin Investig. 2018;48(6):e12927. Scholar
  50. 50.
    Woon PY, Kaisaki PJ, Braganca J, Bihoreau MT, Levy JC, Farrall M, et al. Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proc Natl Acad Sci U S A. 2007;104(36):14412–7. Scholar
  51. 51.
    • Strohmaier S, Devore EE, Zhang Y, Schernhammer ES. A review of data of findings on night shift work and the development of DM and CVD events: a synthesis of the proposed molecular mechanisms. Curr Diab Rep. 2018;18(12):132. This critical review article incorporates several meta-analyses to support the thesis that shift work and behavioral traits associated with circadian disruption offer unique intervention options in the treatment of diabetes and cardiovascular disease. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature. 2010;466(7306):627–31. Scholar
  53. 53.
    •• Hou T, Su W, Guo Z, Gong MC. A novel diabetic mouse model for real-time monitoring of clock gene oscillation and blood pressure circadian rhythm. J Biol Rhythm. 2018;748730418803719. This important study establishes a novel model for combining the study of diabetic complications with circadian biology. CrossRefGoogle Scholar
  54. 54.
    Su W, Xie Z, Guo Z, Duncan MJ, Lutshumba J, Gong MC. Altered clock gene expression and vascular smooth muscle diurnal contractile variations in type 2 diabetic db/db mice. Am J Physiol Heart Circ Physiol. 2012;302(3):H621–33. Scholar
  55. 55.
    Su W, Guo Z, Randall DC, Cassis L, Brown DR, Gong MC. Hypertension and disrupted blood pressure circadian rhythm in type 2 diabetic db/db mice. Am J Physiol Heart Circ Physiol. 2008;295(4):H1634–41. Scholar
  56. 56.
    Cooper ME. Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia. 2001;44(11):1957–72. Scholar
  57. 57.
    Wolf G. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Investig. 2004;34(12):785–96. Scholar
  58. 58.
    Martini S, Eichinger F, Nair V, Kretzler M. Defining human diabetic nephropathy on the molecular level: integration of transcriptomic profiles with biological knowledge. Rev Endocr Metab Disord. 2008;9(4):267–74. Scholar
  59. 59.
    Whaley-Connell A, Sowers JR, McCullough PA, Roberts T, McFarlane SI, Chen SC, et al. Diabetes mellitus and CKD awareness: the Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES). Am J Kidney Dis. 2009;53(4 Suppl 4):S11–21. Scholar
  60. 60.
    Matovinovic MS. 1Pathophysiology and classification of kidney diseases. EJIFCC. 2009;20(1):2–11.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Garcia-Perez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7(6):327–40. Scholar
  62. 62.
    Moore WV, Donaldson DL, Chonko AM, Ideus P, Wiegmann TB. Ambulatory blood pressure in type I diabetes mellitus. Comparison to presence of incipient nephropathy in adolescents and young adults. Diabetes. 1992;41(9):1035–41.CrossRefGoogle Scholar
  63. 63.
    Ayala DE, Moya A, Crespo JJ, Castineira C, Dominguez-Sardina M, Gomara S, et al. Circadian pattern of ambulatory blood pressure in hypertensive patients with and without type 2 diabetes. Chronobiol Int. 2013;30(1–2):99–115. Scholar
  64. 64.
    Hansen HP, Rossing P, Tarnow L, Nielsen FS, Jensen BR, Parving HH. Circadian rhythm of arterial blood pressure and albuminuria in diabetic nephropathy. Kidney Int. 1996;50(2):579–85.CrossRefGoogle Scholar
  65. 65.
    Hermida RC, Ayala DE, Mojon A, Fernandez JR. Influence of time of day of blood pressure-lowering treatment on cardiovascular risk in hypertensive patients with type 2 diabetes. Diabetes Care. 2011;34(6):1270–6. Scholar
  66. 66.
    Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, Hogenesch JB, et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell. 2000;103(7):1009–17.CrossRefGoogle Scholar
  67. 67.
    Rudic RD, McNamara P, Curtis AM, Boston RC, Panda S, Hogenesch JB, et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2004;2(11):e377. Scholar
  68. 68.
    Shimba S, Ogawa T, Hitosugi S, Ichihashi Y, Nakadaira Y, Kobayashi M, et al. Deficient of a clock gene, brain and muscle Arnt-like protein-1 (BMAL1), induces dyslipidemia and ectopic fat formation. PLoS One. 2011;6(9):e25231. Scholar
  69. 69.
    Choudhry H, Harris AL. Advances in hypoxia-inducible factor biology. Cell Metab. 2018;27(2):281–98. Scholar
  70. 70.
    Persson P, Palm F. Hypoxia-inducible factor activation in diabetic kidney disease. Curr Opin Nephrol Hypertens. 2017;26(5):345–50. Scholar
  71. 71.
    Tanaka S, Tanaka T, Nangaku M. Hypoxia and dysregulated angiogenesis in kidney disease. Kidney Dis (Basel, Switzerland). 2015;1(1):80–9. Scholar
  72. 72.
    Gunaratnam L, Bonventre JV. HIF in kidney disease and development. J Am Soc Nephrol. 2009;20(9):1877–87. Scholar
  73. 73.
    Pizarro A, Hayer K, Lahens NF, Hogenesch JB. CircaDB: a database of mammalian circadian gene expression profiles. Nucleic Acids Res. 2013;41(Database issue):D1009–13. Scholar
  74. 74.
    van Zuydam NR, Ahlqvist E, Sandholm N, Deshmukh H, Rayner NW, Abdalla M, et al. A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes. Diabetes. 2018;67(7):1414–27. Scholar
  75. 75.
    Davoudi S, Sobrin L. Novel genetic actors of diabetes-associated microvascular complications: retinopathy, kidney disease and neuropathy. Rev Diabet Stud. 2015;12(3–4):243–59. Scholar
  76. 76.
    Mollsten A, Torffvit O. Tamm-Horsfall protein gene is associated with distal tubular dysfunction in patients with type 1 diabetes. Scand J Urol Nephrol. 2010;44(6):438–44. Scholar
  77. 77.
    Wang Y, Peng W, Zhang X, Qiao H, Wang L, Xu Z, et al. The association of ACE gene polymorphism with diabetic kidney disease and renoprotective efficacy of valsartan. J Renin-Angiotensin-Aldosterone Syst. 2016;17(3).

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Olanrewaju A. Olaoye
    • 1
  • Sarah H. Masten
    • 1
  • Rajesh Mohandas
    • 1
    • 2
  • Michelle L. Gumz
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Medicine, Division of Nephrology, Hypertension, and Renal TransplantationUniversity of FloridaGainesvilleUSA
  2. 2.North Florida/South Georgia Veterans Health SystemGainesvilleUSA
  3. 3.Department of Biochemistry and Molecular BiologyUniversity of FloridaGainesvilleUSA

Personalised recommendations