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Aging renders desynchronization between clock and immune genes in male Wistar rat kidney: chronobiotic role of curcumin

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Abstract

Suprachiasmatic nucleus (SCN) contains the central clock that orchestrate circadian rhythms in physiology and behavior in mammals. Tightly interlocked transcriptional and translational feedback loops (TTFLs) comprising of various clock genes such as Clock, Bmal1, Periods, Cryptochromes etc. in the SCN, send the timing signals to peripheral clocks that governs local metabolism with similar TTFLs. Peripheral clocks in kidney regulates several circadian rhythms like blood pressure, immunity etc. However, aging leads to circadian and inflammatory disorders in kidney. Though there are increasing evidences on age associated perturbations, studies elucidating the rhythmic expression of clock and immune genes across aging in kidney are obscure. We therefore studied changes in daily rhythms of clock and immune genes in kidney. In this study we measured mRNA expression of clock genes rBmal1, rPer1, rPer2, rCry1, rCry2, rRev-erbα, rRorα, and inflammatory genes rNfκb1, rTnfα, rIl6, rTlr4 and rTlr9 in 3, 12 and 24 months male Wistar rat kidney using qRT-PCR. From our study, we did not observe significant changes in clock genes expression except rRorα, but immune genes showed significant phase alterations as well as increase in mean 24 h levels. Pearson correlation analysis of data showed desynchronization between immune and clock genes expression. We further studied the effect of administration of curcumin which has anti-aging, anti-inflammatory, anti-oxidant etc. properties, and evaluated its chronobiotic properties. We here report differential effects of curcumin administration on daily rhythms of clock and immune genes expression.

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References

  • Arjona A, Sarkar DK (2005) Circadian oscillations of clock genes, cytolytic factors, and cytokines in rat NK cells. J Immunol 174:7618–7624

    Article  CAS  PubMed  Google Scholar 

  • Astafev AA, Patel SA, Kondratov RV (2017) Calorie restriction effects on circadian rhythms in gene expression are sex dependent. Sci Rep 7:9716

    Article  PubMed  PubMed Central  Google Scholar 

  • Balsalobre A (2002) Clock genes in mammalian peripheral tissues. Cell Tissue Res 309:193–199

    Article  CAS  PubMed  Google Scholar 

  • Bolignano D, Mattace-Raso F, Sijbrands EJ, Zoccali C (2014) The aging kidney revisited: a systematic review. Ageing Res Rev 14:65–80

    Article  CAS  PubMed  Google Scholar 

  • Cermakian N, Lange T, Golombek D, Sarkar D, Nakao A, Shibata S, Mazzoccoli G (2013) Crosstalk between the circadian clock circuitry and the immune system. Chronobiol Int 30:870–888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Kieswich JE, Chiazza F, Moyes AJ, Gobbetti T, Purvis GS, Salvatori DC, Patel NS, Perretti M, Hobbs AJ, Collino M (2016) IκB kinase inhibitor attenuates sepsis-induced cardiac dysfunction in CKD. J Am Soc Nephrol 28:94–105

    Article  PubMed  PubMed Central  Google Scholar 

  • Chomczynski P, Sacchi N (2006) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction: twenty-something years on. Nat Protoc 1:581–585

    Article  CAS  PubMed  Google Scholar 

  • Christiansen SL, Bouzinova EV, Fahrenkrug J, Wiborg O (2016) Altered expression pattern of clock genes in a rat model of depression. Int J Neuropsychopharmacol. https://doi.org/10.1093/ijnp/pyw061

    Article  PubMed  PubMed Central  Google Scholar 

  • Curtis AM, Bellet MM, Sassone-Corsi P, O’Neill LA (2014) Circadian clock proteins and immunity. Immunity 40:178–186

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Doi M, Takahashi Y, Komatsu R, Yamazaki F, Yamada H, Haraguchi S, Emoto N, Okuno Y, Tsujimoto G, Kanematsu A, Ogawa O (2010) Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6. Nat Med 16:67–74

    Article  CAS  PubMed  Google Scholar 

  • Douma LG, Cheng KY, Lynch IJ, Holzworth M, Masten S, Barral D, Miller A, Esser KA, Wingo CS, Gumz ML (2018) Kidney-specific KO of the circadian clock protein BMAL1 lowers blood pressure in male C57BL/6 J mice. FASEB J 32(1_supplement):905–906

    Google Scholar 

  • Fontaine C, Rigamonti E, Pourcet B, Duez H, Duhem C, Fruchart JC, Chinetti-Gbaguidi G, Staels B (2008) The nuclear receptor Rev-erbα is a liver X receptor (LXR) target gene driving a negative feedback loop on select LXR-induced pathways in human macrophages. Mol Endocrinol 22:1797–1811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gumz ML, Stow LR, Lynch IJ, Greenlee MM, Rudin A, Cain BD, Weaver DR, Wingo CS (2009) The circadian clock protein Period 1 regulates expression of the renal epithelial sodium channel in mice. J Clin Invest 119:2423–2434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haloui M, Tremblay J, Seda O, Koltsova SV, Maksimov GV, Orlov SN, Hamet P (2013) Increased renal epithelial Na channel expression and activity correlate with elevation of blood pressure in spontaneously hypertensive rats. Hypertension 62:731–737

    Article  CAS  PubMed  Google Scholar 

  • Hara M, Minami Y, Ohashi M, Tsuchiya Y, Kusaba T, Tamagaki K, Koike N, Umemura Y, Inokawa H, Yagita K (2017) Robust circadian clock oscillation and osmotic rhythms in inner medulla reflecting cortico-medullary osmotic gradient rhythm in rodent kidney. Sci Rep 7:7306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hart EC, Charkoudian N (2014) Sympathetic neural regulation of blood pressure:influences of sex and aging. Physiology (Bethesda) 29:8–15

    CAS  Google Scholar 

  • Hatori M, Gronfier C, Van Gelder RN, Bernstein PS, Carreras J, Panda S, Marks F, Sliney D, Hunt CE, Hirota T, Furukawa T (2017) Global rise of potential health hazards caused by blue light-induced circadian disruption in modern aging societies. NPJ Aging Mech Dis 3:9

    Article  PubMed  PubMed Central  Google Scholar 

  • Hewlings SJ, Kalman DS (2017) Curcumin: a review of its’ effects on human health. Foods 6:92

    Article  CAS  PubMed Central  Google Scholar 

  • Hoesel B, Schmid JA (2013) The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 12:86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jagota A (2012) Age-induced alterations in biological clock:therapeutic effects of melatonin. In: Thakur MK, Rattan SIS (eds) Brain aging and therapeutic interventions. Springer, London, pp 111–129

    Chapter  Google Scholar 

  • Keller M, Mazuch J, Abraham U, Eom GD, Herzog ED, Volk HD, Kramer A, Maier B (2009) A circadian clock in macrophages controls inflammatory immune responses. Proc Natl Acad Sci USA 106:21407–21412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kukkemane K, Jagota A (2019) Therapeutic effects of curcumin on age-induced alterations in daily rhythms of clock genes and Sirt1 expression in the SCN of male Wistar rats. Biogerentology. https://doi.org/10.1007/s10522-018-0979-y

    Article  Google Scholar 

  • Mattam U, Jagota A (2014) Differential role of melatonin in restoration of age-induced alterations in daily rhythms of expression of various clock genes in suprachiasmatic nucleus of male Wistar rats. Biogerontology 15:257–268

    Article  CAS  PubMed  Google Scholar 

  • Narasimamurthy R, Hatori M, Nayak SK, Liu F, Panda S, Verma IM (2012) Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines. Proc Natl Acad Sci USA 109:12662–12667

    Article  PubMed  PubMed Central  Google Scholar 

  • Paladino N, Mul Fedele ML, Duhart JM, Marpegan L, Golombek DA (2014) Modulation of mammalian circadian rhythms by tumor necrosis factor-α. Chronobiol Int 31:668–679

    Article  CAS  PubMed  Google Scholar 

  • Pizarro A, Hayer K, Lahens NF, Hogenesch JB (2013) CircaDB: a database of mammalian circadian gene expression profiles. Nucleic Acids Res 41:1009–1013

    Article  CAS  Google Scholar 

  • Roenneberg T, Merrow M (2016) The circadian clock and human health. Curr Biol 26:432–443

    Article  CAS  Google Scholar 

  • Saifur Rohman M, Emoto N, Nonaka H, Okura R, Nishimura M, Yagita K, van der Horst GT, Matsuo M, Okamura H, Yokoyama M (2005) Circadian clock genes directly regulate expression of the Na(+)/H(+) exchanger NHE3 in the kidney. Kidney Int 67:1410–1419

    Article  PubMed  Google Scholar 

  • Scheiermann C, Kunisaki Y, Frenette PS (2013) Circadian control of the immune system. Nat Rev Immunol 13:190–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schibler U, Gotic I, Saini C, Gos P, Curie T, Emmenegger Y, Sinturel F, Gosselin P, Gerber A, Fleury-Olela F, Rando G (2015) Clock-talk: interactions between central and peripheral circadian oscillators in mammals. Cold Spring Harb Symp Quant Biol 80:223–232

    Article  PubMed  Google Scholar 

  • Silver AC, Arjona A, Walker WE, Fikrig E (2012) The circadian clock controls toll-like receptor 9-mediated innate and adaptive immunity. Immunity 36:251–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silver AC, Buckley SM, Hughes ME, Hastings AK, Nitabach MN, Fikrig E (2018) Daily oscillations in expression and responsiveness of Toll-like receptors in splenic immune cells. Heliyon 4:e00579

    Article  PubMed  PubMed Central  Google Scholar 

  • Solt LA, Kojetin DJ, Burris TP (2011) The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis. Future Med Chem 3:623–638

    Article  CAS  PubMed  Google Scholar 

  • Spengler ML, Kuropatwinski KK, Comas M, Gasparian AV, Fedtsova N, Gleiberman AS, Gitlin II, Artemicheva NM, Deluca KA, Gudkov AV, Antoch MP (2012) Core circadian protein CLOCK is a positive regulator of NF-κB-mediated transcription. Proc Natl Acad Sci USA 109:2457–2465

    Article  Google Scholar 

  • Stow LR, Gumz ML (2011) The circadian clock in the kidney. J Am Soc Nephrol 22:598–604

    Article  CAS  PubMed  Google Scholar 

  • Sugimoto T, Morioka N, Zhang FF, Sato K, Abe H, Hisaoka-Nakashima K, Nakata Y (2014) Clock gene Per1 regulates the production of CCL2 and interleukin-6 through p38, JNK1 and NF-κB activation in spinal astrocytes. Mol Cell Neurosci 59:37–46

    Article  CAS  PubMed  Google Scholar 

  • Takahashi JS (2017) Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet 18:164–179

    Article  CAS  PubMed  Google Scholar 

  • Takeda Y, Jothi R, Birault V, Jetten AM (2012) RORγ directly regulates the circadian expression of clock genes and downstream targets in vivo. Nucleic Acids Res 40:8519–8535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD (2011) NF-κB in aging and disease. Aging Dis 2:449–465

    PubMed  PubMed Central  Google Scholar 

  • Tognini P, Murakami M, Sassone-Corsi P (2018) Interplay between microbes and the circadian clock. Cold Spring Harb Perspect Biol 10:a028365

    Article  PubMed  PubMed Central  Google Scholar 

  • Vinod C, Jagota A (2017) Daily Socs1 rhythms alter with aging differentially in peripheral clocks in male Wistar rats: therapeutic effects of melatonin. Biogerontology 18:333–345

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Li J, Gai Z, Kullak-Ublick GA, Liu Z (2017) TNF-α deficiency prevents renal inflammation and oxidative stress in obese mice. Kidney Blood Press Res 42:416–427

    Article  CAS  PubMed  Google Scholar 

  • Wardyn JD, Ponsford AH, Sanderson CM (2015) Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways. Biochem Soc Trans 43:621–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xi Y, Shao F, Bai XY, Cai G, Lv Y, Chen X (2014) Changes in the expression of the Toll-like receptor system in the aging rat kidneys. PLoS ONE 9:e96351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang L, Chu Y, Wang LA, Wang Y, Zhao X, He W, Zhang P, Yang X, Liu X, Tian L, Li B (2015) Overexpression of CRY1 protects against the development of atherosclerosis via the TLR/NF-κB pathway. Int Immunopharmacol 28:525–530

    Article  CAS  PubMed  Google Scholar 

  • Yang G, Chen L, Grant GR, Paschos G, Song WL, Musiek ES, Lee V, McLoughlin SC, Grosser T, Cotsarelis G, FitzGerald GA (2016) Timing of expression of the core clock gene Bmal1 influences its effects on aging and survival. Sci Transl Med 8(324):324ra16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu HT, Bian C, Yuan JC, Chu WH, Xiang X, Chen F, Wang CS, Feng H, Lin JK (2014) Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury. J Neuroinflamm 11:59

    Article  CAS  Google Scholar 

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Acknowledgement

The work is supported by ICMR grant (Ref. No. 55/7/2012-/BMS) to AJ. AJ is also thankful to DST Purse Grant to University of Hyderabad. NBT is thankful to UGC for SRF.

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  1. Neurobiology and Molecular Chronobiology Laboratory, Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India

    Neelesh Babu Thummadi & Anita Jagota

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  1. Neelesh Babu Thummadi
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Correspondence to Anita Jagota.

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10522_2019_9813_MOESM1_ESM.pptx

Supplementary material 1—Melt curves of all the genes studied. Single peak represents specific amplification (PPTX 958 kb)

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Thummadi, N.B., Jagota, A. Aging renders desynchronization between clock and immune genes in male Wistar rat kidney: chronobiotic role of curcumin. Biogerontology 20, 515–532 (2019). https://doi.org/10.1007/s10522-019-09813-6

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