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The Circadian Clock in the Kidney

Lisa R. Stow* and Michelle L. Gumz†

*Biochemistry and Molecular Biology and †Medicine, Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, Florida

ABSTRACT Circadian variations in renal function were first described in the 19th century, and GFR, thought to allow crosstalk between physi- renal blood flow, urine production, and electrolyte excretion exhibit daily oscillations. ology and the clock.5,7 In addition to reg- These clinical observations are well established, but the underlying mechanisms that ulating each other to maintain oscilla- govern circadian fluctuations in kidney are not fully understood. Here we provide a tion, the core clock proteins regulate brief overview of the machinery governing the circadian clock and examine the clinical genes that mediate physiologic func- and molecular evidence supporting a critical role for circadian rhythm in the kidney. tions governed by circadian rhythm. There is a connection between BP oscillation and renal disease that supports the use These clock-controlled output genes of chronotherapy in the treatment of hypertension or correction of nondipping BP. constitute up to 15% of expressed tran- Such studies support a developing model of clock controlled sodium and water scripts in some tissues.8 transport in renal epithelial cells. Recent advances in identifying novel clock-controlled The core clock machinery has been genes using rodent and cellular models also shed light on the molecular mechanisms identified in nearly every peripheral tis- by which the circadian clock controls renal function; however, the field is new and sue. The master clock in the SCN syn- much more work remains. chronizes the functions of these periph- eral clocks through neuronal and J Am Soc Nephrol 22: 598–604, 2011. doi: 10.1681/ASN.2010080803 humoral signaling.9 As well, body tem- perature, rest-activity cycles, and feeding cycles contribute to entrainment of the Most physiologic processes, including sleep- The master pacemaker of the circadian peripheral clocks. Although the relation- wake patterns, heartbeat, and systemic ar- clock is located in the suprachiasmatic nu- ship between the central and peripheral terial BP, exhibit a circadian pattern of cleus (SCN) of the brain. This central clock clocks has been described as co-dependent, variation. The word circadian is derived is entrained by light signals transmitted the peripheral clocks do not respond iden- from the Latin words circa and dies, mean- from the retina through the retinohypo- tically to cues from the SCN.10–12 Thus, ing about a day. The term circadian is used thalamic tract. A core group of clock study of the clock in individual tissues is here to denote biologic processes that oc- genes functions in a series of transcrip- necessary. The role of circadian rhythms cur with a daily, or approximately a 24- tion-based feedback loops (Figure 1). has recently been reviewed for the cardio- hour rhythm. A more stringent definition Transcription factors, Bmal1 and Clock, vascular system,13 the vasculature,14,15 of circadian is used in studies of biologic drive the transcription of the Period (Per1, metabolic syndrome,16 and the gastroin- rhythms to describe oscillations that occur 2, and 3) and Cryptochrome (Cry1 and 2) testinal system.17 Here we examine the under constant conditions; a process is genes and nuclear receptor genes, ROR and clinical and molecular evidence supporting considered truly circadian only if the oscil- Rev-erb␣. The Bmal1/Clock heterodimer a critical role for the clock in the control of lation is maintained in the absence of ex- regulates gene expression by binding renal function. ternal zeitgeibers, or time cues such as E-box response elements (CANNTG) in light/dark cycles. It has been over a century the promoter region of target genes. Period since Vogel first reported daily fluctuations in and Cryptochrome inhibit Bmal1 and urine volume.1 Healthy individuals excrete Clock action, thereby repressing their own Published online ahead of print. Publication date more electrolytes and produce more urine transcription, whereas ROR and Rev-erb␣ available at www.jasn.org. during the day than at night, and there are mediate opposing action on Bmal1 ex- Correspondence: Dr. Michelle L. Gumz, 1600 SW 5,6 Archer Road, Box 100224, Gainesville, FL 32610. diurnal rhythms for urinary sodium, potas- pression. Post-translational modifica- Phone: 352-273-6887; Fax: 352-392-3581; E-mail: sium, and chloride excretion.2 Disruption of tion controls stability and nuclear entry of [email protected]

these patterns is often associated with hyper- clock proteins, contributes to the precise Copyright © 2011 by the American Society of tension and cardiovascular disease.3,4 timing of the clock mechanism, and is Nephrology

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rectly correlates with a nondipping phenotype. A well-controlled study showed that creatinine clearance de- CYTOPLASM Per Cry clines more rapidly in nondippers com- pared with dippers, and urinary protein Bmal1 Clock excretion is greater in the nondippers E-box per compared with dippers.32 The nondip- Bmal1 Clock ROR E-box cry ping phenotype also associates with a faster decline in renal function, and the Bmal1 Clock ror Rev- authors suggested that regulation of E-box erbα nocturnal BP should be an additional Bmal1 Clock goal of anti-hypertensive treatment. E-box nr1d1 Bmal1 Similarly, Agarwal and Light33 deter-

bmal1 RRE mined that a nondipping status was a significant predictor of chronic kidney disease and proteinuria and inferred NUCLEUS that correction of dipper status could be an effective therapy for kidney dis- ease. Taken together, these studies showed the important relationship be- Figure 1. Transcriptional mechanism of the circadian clock. Bmal1 and Clock het- tween renal physiology and the circa- erodimerize to positively regulate expression of the Period (per) and Cryptochrome (cry) dian pattern of BP. gene families, as well as the retinoic acid orphan receptor (ror) and Nr1d1 (rev-erb␣) genes. Per/Cry inhibit Bmal1/Clock action to repress their own transcription, whereas Chronotherapy in the Treatment of ␣ ROR and Rev-erb mediate opposing action on bmal1 gene expression. Expression Hypertension of the Clock protein is constitutive in many tissues. Bmal1/Clock action is mediated Increasing evidence supports a critical role through binding of E-box response elements (CANNTG) in the promoters of target genes. for the circadian clock in human health. Chronotherapy, the scheduled administra- tion of pharmaceutical agents with respect ROLE OF THE CIRCADIAN CLOCK changes in BP. Patients suffering from al- to an individual’s circadian rhythms, may IN THE KIDNEY: CLINICAL dosteronism exhibit the nondipper pat- increase the effectiveness and decrease the EVIDENCE tern,22,23 and treatment with the angio- side effects of pharmacologic agents.34,35 tension II receptor blocker, irbesartan Chronotherapy has been investigated in the Nondipping BP and the Kidney corrects the nondipper pattern in salt- treatment of many nonrenal diseases36–40 Cardiovascular events such as stroke and sensitive hypertension.24 The diuretic and has been proposed for treatment of myocardial infarction are known to peak hydrocholorothiazide restores an appro- diabetes,41 cardiac arrhythmias,42 and with the morning surge in BP and heart priate decrease in nocturnal BP in non- ischemic heart disease.43 rate. BP increases in the early morning, fol- dipping patients but had no effect in dip- The potential benefits of chrono- lowed by a plateau during the day, and then pers.25 Furthermore, dietary sodium therapy in the treatment of hypertension dips during sleep.18 Patients who do not restriction re-establishes the nocturnal include control of BP and normalization exhibit a 10 to 20% decrease in nighttime dipping pattern.26 Nondipping associ- of the dipping pattern.44 Cross-sectional versus daytime BP are designated “nondip- ates with an increased risk of nephropa- and longitudinal studies consistently pers” and are at increased risk of cardiac thy27 and chronic kidney disease.28 Impor- show that nondipping is a preclinical death.19 Nondippers exhibit increased left tantly, renal transplantation can rescue the marker for cardiovascular and renal dis- ventricular hypertrophy, carotid artery nondipping phenotype,29 although a lack ease and can be used to predict cardio- wall thickness and atherosclerotic plaques, of nocturnal variation can portend poor al- vascular events.45 Indeed, accruing evi- microalbuminuria, cerebrovascular dis- lograft survival.30 Collectively, these findings dence suggests that nighttime BP is a ease, congestive heart failure, vascular de- suggest a direct link between abnormal circa- more important indicator of cardiovas- mentia, stroke, and myocardial infarc- dian patterns in BP and inappropriate so- cular health than daytime values.46,47 tion.20 Importantly, nondipping may dium transport in the kidney. One example comes from a convincing predict renal damage.21 Salt handling by the kidney has long study in which previously untreated hy- Several reports link aldosterone sig- been recognized as a critical determinant pertensive patients were randomized naling to the disruption of circadian BP of BP, and hypertension is rarely ob- into groups receiving a single daily dose patterns, suggesting a role for renal func- served in the absence of renal dysfunc- of ramipril either in the morning or at tion in maintaining normal circadian tion.31 A decline in renal function di- bedtime.48 BP during sleep was signifi-

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cantly reduced in bedtime-dosed pa- tients. Interestingly, patients receiving acid oscillates with a circadian pattern.60,61 tients compared with morning-dosed nocturnal dialysis experienced the nor- Although these clinical observations have patients. Notably, nighttime dosing also mal nighttime peak in melatonin and been well established, the underlying mo- increases the effectiveness of ramipril as reported better sleep quality compared lecular mechanisms are unclear. BP reduction lasted 24 hours after bed- with daytime dialysis patients.55 A re- time dosing compared with 16 hours af- cent study in patients with chonic kid- ter morning dosing. ney disease (CKD) found that melatonin MOLECULAR EVIDENCE FOR THE The effect of nighttime administration amplitude decreases with advancing renal ROLE OF A CIRCADIAN CLOCK IN of anti-hypertensive drugs in nondipping disease, emphasizing the need for further THE KIDNEY patients has been tested in geographically investigation into circadian mechanisms in distinct populations.49,50,51 Anti-hyperten- CKD patients.55 Transcriptional Regulation of Renal sive therapy delivered as an evening dose is Patients undergoing dialysis treat- Gene Expression by the Circadian highly effective at correcting the nondip- ment are more prone to sleep distur- Clock ping phenotype. Bedtime administration bances compared with the general popu- A growing number of genes are regulated of valsartan, doxazosin (extended release), lation, resulting in a negative impact on by transcriptional mechanisms of the cir- torasemid, or long-acting nifedipine im- overall health and quality of life. Non- cadian clock. Many clock-controlled genes proves efficacy and reduces side effects of dipping CKD patients seem to have poor have been identified in the kidney through anti-hypertensive treatment.52 These stud- sleep quality.56 Circadian sleep-wake dis- either gene expression profiling or candi- ies highlight the importance of evaluating turbances are common in ESRD pa- date gene approaches (Table 1). The term the 24-hour BP profile as opposed to sin- tients.57 Renal disease and dialysis treat- “clock-controlled gene” is used here to de- gle, daytime office measurements. Al- ment may contribute to the etiology of scribe genes that exhibit rhythmic expres- though these results are promising, larger, sleep disturbances in dialysis patients in- sion. Most of the genes listed in Table 1 more comprehensive trials are needed. A dependently of each other. Up to 80% of have only recently been linked to the circa- reduction in all-cause mortality would be a ESRD patients have reported subjective dian clock, and it remains to be determined convincing outcome. A long-term study sleep problems. Daytime sleepiness is in- whether circadian clock proteins interact following thousands of subjects, the re- creased by dialysis, and this effect is the with E-box elements in the promoters of cently completed Monitorizacio´n Ambu- result of several factors, including ele- these genes. latoria de la Presio´ n Arterial y Eventos Car- vated body temperature during treat- These genes encode products that diovasculares—Ambulatory Blood Pressure ment and the physical and emotional range from transcription regulators62 Monitoring and Cardiovascular Events stress caused by the procedure. Likewise, to cell junction proteins.63,64 Although (MAPEC) trial, was designed to determine sleep disturbances are a common side the implications of clock-mediated whether restoring the dipper pattern using effect of medications prescribed to regulation of these genes are not yet chronotherapy decreases the risk of cardio- ESRD patients, including ␤-blockers clear, it is interesting that the function vascular disease.53 Providing evidence for the and benzodiazepines. Several treat- of the transcription repressor, Kid-1 use of chronotherapy in hypertension, the ments aimed at resynchronizing the (kidney, ischemia, developmentally- MAPEC results demonstrate that bedtime sleep-wake rhythm in hemodialysis pa- regulated gene 1),65 is linked to regula- drug administration, compared to conven- tients result in some level of sleep im- tion of extracellular signal-regulated tional upon-awakening therapy, was more provement.57 These include a switch to kinases,66 providing an intriguing link effective at controlling BP and decreasing nocturnal hemodialysis, lowering the between a clock-controlled gene and non-dipping, and resulted in significant re- temperature of the dialyzate, exercise signal transduction in the kidney. Fur- duction of cardiovascular morbidity and during dialysis, administration of mel- thermore, the rhythmic expression of mortality.54 atonin, or exogenous erythropoietin E-cadherin and claudin-4 seemed to treatment. Bright light therapy might parallel the circadian changes observed Circadian Disturbances in Dialysis also benefit hemodialysis patients with in sodium excretion.63 Patients circadian sleep disruption.57 The circadian clock gene Period 1 Melatonin is an important regulator of (Per1) was identified as a novel aldoste- the circadian sleep-wake cycle. In Circadian Influence on Renal rone target in a murine inner medullary healthy individuals, the pineal gland Function collecting duct cell line and was the most produces melatonin at night; light ex- In addition to a role for the kidney in main- highly induced transcript in the entire posure suppresses melatonin produc- taining proper BP rhythms, renal function study.67 Per1 contributes to the basal and tion. The expected nighttime peak in oscillates in a circadian manner with daily aldosterone-dependent transcription of melatonin levels is lost in patients un- fluctuations in renal blood flow and GFR58 Scnn1a, which encodes the rate-limiting dergoing hemodialysis, and decreased and the excretion of electrolytes such as so- subunit of the epithelial sodium chan- melatonin levels associate with more dium and potassium.59 Likewise, urinary nel.68 Scnn1a expression is reduced in the severe sleep disturbances in these pa- excretion of phosphate, magnesium, and renal medulla of Per1 null mice. Per1-

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Table 1. Clock-controlled genes in the kidney dium and water transport (Figure 2). Fur- Gene Function RNA Source Reference ther study will likely identify additional Dec1 bHLH transcription factor Whole kidney 59 clock-controlled genes, providing addi- Dec2 bHLH transcription factor Whole kidney 59 tional insight into the mechanism by Npas2 bHLH transcription factor Whole kidney 59 which the circadian clock regulates water Dbp Albumin Dsite binding protein Whole kidney 59 and electrolyte transport in the kidney. Cldn4 Claudin 4,Tight junction protein Whole kidney 60 E-cadherin Adherens junctions Whole kidney 60 Rodent Models of Circadian Kid-1 Zn finger transcription repressor Whole kidney 63 61 Disorganization Cldn8 Claudin 8, Tight junction protein DCT, CNT Casein kinase I␧-mediated phosphoryla- 61 Mapre2 Microtubule associated protein DCT, CNT, CCD, tion controls stability of the Period pro- whole kidney teins. tau mutant hamsters have a gain-of- Ptges Prostaglandin E synthase DCT, CNT 61 61 function mutation in casein kinase I␧ and Tfrc Transferrin receptor DCT, CNT, CCD, whole kidney display a shortened circadian period. bHLH, basic helix-loop-helix; DCT, distal convoluted tubule; CNT, connecting tubule; CCD, cortical Heterozygous tau mutants display a severe collecting duct. cardiorenal phenotype characterized by cardiomyopathy, hypertrophy, cardiac fi- null mice excrete more urinary sodium tion of NHE3 promoter activity. Consis- brosis, and early death71; renal dysfunction than wild-type mice, although the mech- tent with this observation is a recent re- is manifested as proteinuria, tubular dila- anism of this effect is unknown. The ap- port describing the presence of an E-box tion, glomerular ischemia, and cellular ap- parent circadian expression of Scnn1a is in the Scnn1a promoter that is bound by optosis. SCN ablation in young adult tau also altered in mice lacking all three Pe- Clock and Per1.70 Together these studies mutant hamsters rescues the cardiac hy- riod genes compared with wild-type provide direct molecular evidence for pertrophy phenotype. Moreover, the car- mice. Given the critical role of the rate- regulation of transport gene expression diorenal phenotype is reversed and longev- limiting subunit of the epithelial sodium by the circadian clock. ity is restored when the tau mutants are channel in sodium transport and BP In the first study of its kind, Zuber et maintained on a shorter 22-hour light/ control, these results implicate the clock al.64 used microarray analysis to profile the dark cycle. in the mechanism underlying the known expression of circadian genes in microdis- The mouse renin transgenic rat [TGR(m- daily fluctuations in sodium excretion sected distal nephron and collecting duct REN2)27] is also a well-characterized model and BP. segments over a 24-hour period. Hun- of hypertension. These animals have an in- Many renal transport genes have dreds of putative clock-controlled genes verted circadian BP profile and consequent been identified as clock-controlled were identified. Circadian expression of se- end-organ damage.72 TGR rats exhibit a pro- genes (Table 2). NHE3 was the first lected genes was confirmed in independent found circadian phenotype in which the nor- transporter in the kidney to be identified samples, and these genes are included in mal circadian pattern of core clock gene ex- as a target of the clock transcription Tables 1 and 2. These novel clock targets pression, signal transduction pathways, and mechanism.69 mRNA encoding NHE3 is encode moieties ranging from known reg- sympathetic nervous system activity is altered expressed in a circadian manner in wild- ulators of sodium transport to critical reg- severely.73 Consistent with human studies type rodents, but rhythmic expression is ulators of water balance. Many of the genes discussed above, the renin-angiotensin-aldo- blunted in Cry1/Cry2-null mice. A spe- listed in Table 2 are expressed in principal sterone system contributes to maintenance cific E-box response element is required cells of the cortical collecting duct, and the of circadian rhythms in rodents. for Bmal1/Clock-mediated transactiva- products of these genes contribute to so- Reports of BP phenotypes in rodents

Table 2. Clock-controlled transport genes in the kidney Gene Function RNA Source Reference Slc9a3 (NHE3) Sodium/hydrogen exchange Whole kidney 66 Gilz Leucine zipper protein/regulation of sodium transport DCT, CNT, CCD. Whole kidney 61 Usp2 Ubiquitin specific protease/regulation of sodium transport DCT, CNT, CCD. Whole kidney 61 V1aR Vasopressin receptor/regulation of water balance DCT, CNT, CCD. Whole kidney 61 V2R Vasopressin receptor/regulation of water balance DCT, CNT, CCD. Whole kidney 61 Slc6a6 Taurine transporter CCD 61 Slc6a9 Glycine transporter DCT/CNT 61 Aqp2 Water channel CCD 61 Aqp4 Water channel CCD 61 Scnn1a (␣ENaC) Alpha subunit of epithelial sodium channel Cortex, outer medulla and inner medulla 65 DCT, distal convoluted tubule; CNT, connecting tubule; CCD, cortical collecting duct.

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THE FUTURE

LUMEN BLOOD A critical issue is what proportion of circa- dian fluctuations in renal function is caused by the influence of the central clock

V2R in the SCN versus an intrinsic clock in the kidney alone. Renal tissue explants from V1aR SGK1 H2OH2O Per2/luciferase transgenic mice oscillate in culture, and this effect is maintained after H O H2O AQP-4 2 Nedd4-2 SCN ablation.10 Uncoupling of the periph- AQP-2 ATP + 3 Na+ 3 Na eral clocks from the central clock by food β ET-1 restriction is another way to address this Na+ α α Na+ γ issue. Reversal of the light/dark cycle and

+ ENaC 2 K+ 2 K the feeding schedule causes a phase shift in ADP + Pi the expression of clock genes in rat kid- + + Usp2 K K ney.76 Per1 and Clock appeared to be the GILZ most sensitive to these changes. An impor- + K K+ tant tool in determining the role of the CI CI clock in individual tissues is the generation CI CI of tissue specific null mice. Indeed, pancre- KCC as-deficient Bmal1 mice develop diabetes mellitus,77 and knockout of Clock in cardi- omyocytes alters the normal circadian rhythm of cardiac output, heart rate, and BP.7 Future studies using kidney-deficient Figure 2. Mechanisms of sodium, potassium, chloride, and water transport in a cortical clock genes will be critical to our under- collecting duct principal cell. Proteins denoted by the symbol are the products of genes standing of how the circadian clock regu- ϩ ϩ Ϫ that are expressed in an apparent circadian pattern. Na , sodium; K , potassium; Cl , lates renal function.

chloride; H2O, water; ENaC, epithelial sodium channel; GILZ, glucocorticoid-induced leucine In addition to the transcriptional and zipper protein; Usp2, ubiquitin-specific protease 2; SGK1, serum and glucocorticoid- post-translational regulation of the clock regulated kinase; ET-1, endothelin-1; Nedd4–2, neural precursor cell expressed, devel- mechanism discussed above, microRNAs opmentally downregulated gene 4-like; V1aR, vasopressin 1a receptor; V2R, vasopressin (miRNAs), which regulate mRNA stability 2 receptor. and therefore protein expression, may play a role in the modulation of circadian with circadian clock disruption suggest evated plasma aldosterone levels were rhythms.78 In mammalian cell models, that the clock is critical for cardiovascu- observed in these mice, leading the inves- miRNA-192/194 regulates the expression lar function. Whereas Clock-null mice tigators to perform microarray analysis of the Period gene family.79 Overexpression maintain a normal 24-hour rhythm of of adrenal glands from Cry1/Cry2-null of this miRNA causes a shortened circa- BP, the average mean arterial pressure mice compared with wild type. Hsd3b6,a dian period. Very little is known about and mean systolic BP were significantly dehydrogenase-isomerase in the aldoste- post-translational control of clock proteins lower in these mice compared with wild rone synthesis pathway, was identified as in the kidney,80 and the role of miRNAs in type.64 These mice display altered rhythms a highly overexpressed gene in null mice. the renal circadian clock has not been ex- in urinary sodium excretion and a mild di- Increased activity of this enzyme was re- plored to date. These dynamic processes abetes insipidus. corded in Cry1/Cry2 knockout mice and likely allow fine-tuning of the clock mech- When maintained on a standard 12- was linked to the observed salt-sensitive anism in a tissue-specific manner. hour light/dark cycle, Per2 mutant mice hypertension. Importantly, this study iden- exhibit decreased 24-hour diastolic BP, in- tified a putative target for interventional ther- creased heart rate, and a decreased differ- apy in hypertensive patients. Given that the CONCLUSIONS ence between day and night BP.71 Under HSD3B6 enzyme catalyzes a relatively early constant darkness, wild-type mice main- reaction in the steroid hormone synthesis Discerning the role of the circadian clock in tained normal 24-hour rhythms in BP, ac- pathway (pregnenolone to progesterone), it the kidney has important implications for the tivity, and heart rate, but Per2 mutant mice will be interesting to see what other steroid design of novel therapies and improvement experienced a shortened circadian period. hormones are elevated in these mice and how of existing treatments for renal disease. Nu- Salt-sensitive hypertension was ob- this defect influences the long-term health of merous trials showed that chronotherapy in served in Cry1/Cry2 knockout mice.75 El- these circadian mutant animals. the treatment of nondippers is effective in re-

602 Journal of the American Society of Nephrology J Am Soc Nephrol 22: 598–604, 2011 www.jasn.org BRIEF REVIEW storing the normal 24-hour rhythm of BP in sues. Proc Natl Acad Sci USA 101: 5339– rhythm of blood pressure from nondipper to many patients. Improved use of 24-hour am- 5346, 2004 dipper in essential hypertension. Circulation 11. Guo H, Brewer JM, Champhekar A, Harris 100: 1635–1638, 1999 bulatory BP monitoring could increase iden- RB, Bittman EL: Differential control of pe- 26. Uzu T, Fujii T, Nishimura M, Kuroda S, Na- tification of nondippers that may benefit ripheral circadian rhythms by suprachias- kamura S, Inenaga T, Kimura G: Determi- from nighttime administration of anti-hy- matic-dependent neural signals. Proc Natl nants of circadian blood pressure rhythm in pertensive medications. Nighttime dialysis Acad Sci USA 102: 3111–3116, 2005 essential hypertension. Am J Hypertens 12: may benefit patients experiencing circadian 12. Guo H, Brewer JM, Lehman MN, Bittman EL: 35–39, 1999 Suprachiasmatic regulation of circadian 27. Fukuda M, Goto N, Kimura G: Hypothesis disruption. To identify those patients most rhythms of gene expression in hamster periph- on renal mechanism of non-dipper pattern likely to benefit from chronotherapeutic in- eral organs: Effects of transplanting the pace- of circadian blood pressure rhythm. Medical tervention, we must gain a more complete maker. J Neurosci 26: 6406–6412, 2006 Hypotheses 67: 802–806, 2006 understanding of the mechanism by which 13. Martino TA, Sole MJ: Molecular time: An 28. Portaluppi F, Montanari L, Massari M, Di Chiara the circadian clock regulates renal function. often overlooked dimension to cardiovascu- V, Capanna M: Loss of nocturnal decline of lar disease. Circ Res 105: 1047–1061, 2009 blood pressure in hypertension due to chronic 14. Rudic RD: Time is of the essence: Vascular renal failure. Am J Hypertens 4: 20–26, 1991 implications of the circadian clock. Circula- 29. Gatzka CD, Schobel HP, Klingbeil AU, Neu- DISCLOSURES tion 120: 1714–1721, 2009 mayer HH, Schmieder RE: Normalization of 15. Rudic RD, Fulton DJ: Pressed for time: The circadian blood pressure profiles after renal We thank Dr. Charles Wingo for helpful discus- circadian clock and hypertension. J Appl transplantation. Transplantation 59: 1270– sions. This work was supported by Grant Physiol 107: 1328–1338, 2009 1274, 1995 K01DK085193 (to M.L.G.). 16. Maury E, Ramsey KM, Bass J: Circadian 30. Wadei HM, Am H, Taler SJ, Cosio FG, Griffin rhythms and metabolic syndrome: From ex- MD, Grande JP, Larson TS, Schwab TR, perimental genetics to human disease. Circ Stegall MD, Textor SC: Diurnal blood pres- Res 106: 447–462, 2010 sure changes one year after kidney trans- REFERENCES 17. Hoogerwerf WA: Role of clock genes in gas- plantation: Relationship to allograft func- trointestinal motility. Am J Physiol 299: tion, histology, and resistive index. JAmSoc 1. Pons M, Cambar J, Waterhouse JM: Renal he- G549–G555, 2010 Nephrol 18: 1607–1615, 2007 modynamic mechanisms of blood pressure 18. White WB: Ambulatory blood pressure mon- 31. Kimura G, Dohi Y, Fukuda M: Salt sensitivity rhythms. Ann NY Acad Sci 783: 95–112, 1996 itoring: Dippers compared with non-dip- and circadian rhythm of blood pressure: The 2. Manchester RC: The diurnal rhythm in water pers. Blood Press Monit 5[Suppl 1]: S17– keys to connect CKD with cardiovascular and mineral exchange. J Clin Invest 12: 995– S23, 2000 events. Hypertens Res 33: 515–520, 2010 1008, 1933 19. Routledge FS, McFetridge-Durdle JA, Dean 32. Timio M, Venanzi S, Lolli S, Lippi G, Verdura 3. Dyer AR, Martin GJ, Burton WN, Levin M, CR: Night-time blood pressure patterns and C, Monarca C, Guerrini E: “Non-dipper” hy- Stamler J: Blood pressure and diurnal varia- target organ damage: A review. Can J Car- pertensive patients and progressive renal in- tion in sodium, potassium, and water excre- diol 23: 132–138, 2007 sufficiency: A 3-year longitudinal study. Clin tion. J Human Hypertens 12: 363–371, 1998 20. Hermida RC, Ayala DE, Portaluppi F: Circa- Nephrol 43: 382–387, 1995 4. Goldman R: Studies in diurnal variation of dian variation of blood pressure: The basis 33. Agarwal R, Light RP: GFR, proteinuria and water and electrolyte excretion: Nocturnal for the chronotherapy of hypertension. Adv circadian blood pressure. Nephrol Dial diuresis of water and sodium in congestive Drug Deliv Rev 59: 904–922, 2007 Transplant 24: 2400–2406, 2009 cardiac failure and cirrhosis of the liver. 21. Garcia-Ortiz L, Gomez-Marcos MA, Martin- 34. Ohdo S: Chronotherapeutic strategy: Rhythm J Clin Invest 30: 1191–1199, 1951 Moreiras J, Gonzalez-Elena LJ, Recio-Rodri- monitoring, manipulation and disruption. Adv 5. Reppert SM, Weaver DR: Coordination of guez JI, Castano-Sanchez Y, Grandes G, Mar- Drug Deliv Rev 62: 859–875, 2010 circadian timing in mammals. Nature 418: tinez-Salgado C: Pulse pressure and nocturnal 35. Takahashi JS, Hong HK, Ko CH, McDearmon EL: 935–941, 2002 fall in blood pressure are predictors of vascu- The genetics of mammalian circadian order and 6. Albrecht U, Eichele G: The mammalian cir- lar, cardiac and renal target organ damage in disorder: Implications for physiology and dis- cadian clock. Curr Opin Genet Develop 13: hypertensive patients (LOD-RISK study). ease. Nat Rev Genet 9: 764–775, 2008 271–277, 2003 Blood Press Monit 14: 145–151, 2009 36. Innominato PF, Levi FA, Bjarnason GA: 7. Duguay D, Cermakian N: The crosstalk be- 22. Takakuwa H, Shimizu K, Izumiya Y, Kato T, Chronotherapy and the molecular clock: tween physiology and circadian clock pro- Nakaya I, Yokoyama H, Kobayashi K, Ise T: Clinical implications in oncology. Adv Drug teins. Chronobiol Int 26: 1479–1513, 2009 Dietary sodium restriction restores nocturnal Deliv Rev 62: 979–1001, 2010 8. Vollmers C, Gill S, DiTacchio L, Pulivarthy reduction of blood pressure in patients with 37. Rana S, Mahmood S: Circadian rhythm and SR, Le HD, Panda S: Time of feeding and the primary aldosteronism. Hypertens Res 25: its role in malignancy. J Circadian Rhythms intrinsic circadian clock drive rhythms in he- 737–742, 2002 8: 3, 2010 patic gene expression. Proc Natl Acad Sci 23. Williams D, Croal B, Furnace J, Ross S, Witte 38. Glass-Marmor L, Paperna T, Ben-Yosef Y, USA 106: 21453–21458, 2009 K, Webster M, Critchen W, Webster J: The Miller A: Chronotherapy using corticoste- 9. Dibner C, Schibler U, Albrecht U: The mamma- prevalence of a raised aldosterone-renin ratio roids for multiple sclerosis relapses. J Neurol lian circadian timing system: Organization and (ARR) among new referrals to a hypertension Neurosurg Psychiat 78: 886–888, 2007 coordination of central and peripheral clocks. clinic. Blood Pressure 15: 164–168, 2006 39. Buttgereit F, Doering G, Schaeffler A, Witte Annu Rev Physiol 72: 517–549, 2010 24. Polonia J, Diogo D, Caupers P, Damasceno S, Sierakowski S, Gromnica-Ihle E, Jeka S, 10. Yoo SH, Yamazaki S, Lowrey PL, Shimomura A: Influence of two doses of irbesartan on Krueger K, Szechinski J, Alten R: Targeting K, Ko CH, Buhr ED, Siepka SM, Hong HK, non-dipper circadian blood pressure rhythm pathophysiological rhythms: Prednisone Oh WJ, Yoo OJ, Menaker M, Takahashi JS: in salt-sensitive black hypertensives under chronotherapy shows sustained efficacy in PERIOD2::LUCIFERASE real-time reporting high salt diet. J Cardiovasc Pharmacol 42: rheumatoid arthritis. Ann Rheum Dis 69: of circadian dynamics reveals persistent cir- 98–104, 2003 1275–1280, 2010 cadian oscillations in mouse peripheral tis- 25. Uzu T, Kimura G: Diuretics shift circadian 40. Smolensky MH, Lemmer B, Reinberg AE:

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Chronobiology and chronotherapy of aller- PM, Kerkhof GA: Different melatonin Okura R, Nishimura M, Yagita K, van der gic rhinitis and bronchial asthma. Adv Drug rhythms and sleep-wake rhythms in patients Horst GT, Matsuo M, Okamura H, Yokoyama Deliv Rev 59: 852–882, 2007 on peritoneal dialysis, daytime hemodialysis M: Circadian clock genes directly regulate 41. Kanat M: Is daytime insulin more physiologic and nocturnal hemodialysis. Sleep Medicine expression of the Na(ϩ)/H(ϩ) exchanger and less atherogenic than bedtime insulin? 11: 242–246, 2010 NHE3 in the kidney. Kidney Int 67: 1410– Med Hypotheses 68: 1228–1232, 2007 56. Agarwal R, Light RP: Physical activity and 1419, 2005 42. Portaluppi F, Hermida RC: Circadian rhythms hemodynamic reactivity in chronic kidney 70. Gumz ML, Cheng K, Lynch IJ, Stow LR, in cardiac arrhythmias and opportunities for disease. Clin J Am Soc Nephrol 3: 1660– Greenlee MM, Cain BD, Wingo CS: Regula- their chronotherapy. Adv Drug Deliv Rev 59: 1668, 2008 tion of ␣ENaC expression by the circadian 940–951, 2007 57. Koch BC, Nagtegaal JE, Kerkhof GA, ter clock protein period 1 in mpkCCDc14 cells. 43. Portaluppi F, Lemmer B: Chronobiology and Wee PM: Circadian sleep-wake rhythm dis- Biochim Biophys Acta 1799: 622–629, 2010 chronotherapy of ischemic heart disease. turbances in end-stage renal disease. Nat 71. Martino TA, Oudit GY, Herzenberg AM, Tata Adv Drug Deliv Rev 59: 952–965, 2007 Rev 5: 407–416, 2009 N, Koletar MM, Kabir GM, Belsham DD, 44. Smolensky MH, Hermida RC, Ayala DE, 58. Vagnucci AH, Shapiro AP, McDonald RH Jr: Backx PH, Ralph MR, Sole MJ: Circadian Tiseo R, Portaluppi F: Administration-time- Effects of upright posture on renal electrolyte rhythm disorganization produces profound dependent effects of blood pressure-lower- cycles. J Appl Physiol 26: 720–731, 1969 cardiovascular and renal disease in ham- ing medications: Basis for the chronotherapy 59. Moore-Ede MC: Physiology of the circadian sters. Am J Physiol Regul Integr Comp of hypertension. Blood Press Monit 15: 173– timing system: Predictive versus reactive ho- Physiol 294: R1675–R1683, 2008 180, 2010 meostasis. Am J Physiol 250: R737–R752, 72. Witte K, Lemmer B: Development of inverse 45. Cuspidi C, Vaccarella A, Leonetti G, Sala C: 1986 circadian blood pressure pattern in trans- Ambulatory blood pressure and diabetes: 60. Min HK, Jones JE, Flink EB: Circadian varia- genic hypertensive TGR(mREN2)27 rats. targeting nondipping. Curr Diabet Rev 6: tions in renal excretion of magnesium, cal- Chronobiol Int 16: 293–303, 1999 111–115, 2010 cium, phosphorus, sodium, and potassium 73. Lemmer B, Witte K, Enzminger H, Schiffer S, 46. Ernst ME: Nighttime blood pressure is the blood during frequent feeding and fasting. Fed Hauptfleisch S: Transgenic TGR(mREN2)27 pressure. Pharmacotherapy 29: 3–6, 2009 Proc 25: 917–921, 1966 rats as a model for disturbed circadian orga- 47. White WB: Relating cardiovascular risk to 61. Cameron MA, Baker LA, Maalouf NM, Moe nization at the level of the brain, the heart, out-of-office blood pressure and the impor- OW, Sakhaee K: Circadian variation in urine and the kidneys. Chronobiol Int 20: 711– tance of controlling blood pressure 24 hours pH and uric acid nephrolithiasis risk. Neph- 738, 2003 a day. Am J Med 121: S2–S7, 2008 rol Dial Transplant 22: 2375–2378, 2007 74. Vukolic A, Antic V, Van Vliet BN, Yang Z, 48. Hermida RC, Ayala DE: Chronotherapy with 62. Noshiro M, Furukawa M, Honma S, Albrecht U, Montani JP: Role of mutation the angiotensin-converting enzyme inhibitor Kawamoto T, Hamada T, Honma K, Kato Y: of the circadian clock gene Per2 in cardio- ramipril in essential hypertension: Improved Tissue-specific disruption of rhythmic ex- vascular circadian rhythms. Am J Physiol blood pressure control with bedtime dosing. pression of Dec1 and Dec2 in clock mutant Regul Integr Comp Physiol, 298: R627– Hypertension 54: 40–46, 2009 mice. J Biol Rhythms 20: 404–418, 2005 R634, 2010 49. Hermida RC, Ayala DE, Fernandez JR, Calvo 63. Yamato M, Ito T, Iwatani H, Yamato M, Imai 75. Doi M, Takahashi Y, Komatsu R, Yamazaki F, C: Chronotherapy improves blood pressure E, Rakugi H: E-cadherin and claudin-4 ex- Yamada H, Haraguchi S, Emoto N, Okuno Y, control and reverts the nondipper pattern in pression has circadian rhythm in adult rat Tsujimoto G, Kanematsu A, Ogawa O, Todo patients with resistant hypertension. Hyper- kidney. J Nephrol 23: 102–110, 2010 T, Tsutsui K, van der Horst GT, Okamura H: tension 51: 69–76, 2008 64. Zuber AM, Centeno G, Pradervand S, Niko- Salt-sensitive hypertension in circadian 50. Minutolo R, Gabbai FB, Borrelli S, Scigliano R, laeva S, Maquelin L, Cardinaux L, Bonny O, clock-deficient Cry-null mice involves dys- Trucillo P, Baldanza D, Laurino S, Mascia S, Firsov D: Molecular clock is involved in pre- regulated adrenal Hsd3b6. Nat Med 16: 67– Conte G, De Nicola L: Changing the timing of dictive circadian adjustment of renal func- 74, 2010 antihypertensive therapy to reduce nocturnal tion. Proc Natl Acad Sci USA, 106: 16523– 76. Wu T, Ni Y, Dong Y, Xu J, Song X, Kato H, Fu blood pressure in CKD: an 8-week uncontrolled 16528, 2009 Z: Regulation of circadian gene expression trial. Am J Kidney Dis 50: 908–917, 2007 65. Witzgall R, O’Leary E, Gessner R, Ouellette AJ, in the kidney by light and food cues in rats. 51. Takeda A, Toda T, Fujii T, Matsui N: Bed- Bonventre JV: Kid-1, a putative renal transcrip- Am J Physiol Regul Integr Comp Physiol, time administration of long-acting antihy- tion factor: Regulation during ontogeny and in 298: R635–R641, 2010 pertensive drugs restores normal nocturnal response to ischemia and toxic injury. Molec 77. Marcheva B, Ramsey KM, Buhr ED, Ko- blood pressure fall in nondippers with es- Cell Biol 13: 1933–1942, 1993 bayashi Y, Su H, Ko CH, Ivanova G, Omura sential hypertension. Clin Exp Nephrol 13: 66. Yamato M, Ishida N, Iwatani H, Yamato M, C, Mo S, Vitaterna MH, Lopez JP, Philipson 467–472, 2009 Rakugi H, Ito T: Kid-1 participates in regu- LH, Bradfield CA, Crosby SD, Jebailey L, 52. Simko F, Pechanova O: Potential roles of lating ERK phosphorylation as a part of the Wang X, Takahashi JS, Bass J: Disruption of melatonin and chronotherapy among the circadian clock output in rat kidney. J Recep- the clock components CLOCK and BMAL1 new trends in hypertension treatment. J Pi- tor Signal Transduction Res 29: 94–99, 2009 leads to hypoinsulinaemia and diabetes. Na- neal Res 47: 127–133, 2009 67. Gumz ML, Popp MP, Wingo CS, Cain BD: ture 466: 627–631, 2010 53. Hermida RC: Ambulatory blood pressure Early transcriptional effects of aldosterone 78. Pegoraro M, Tauber E: The role of microR- monitoring in the prediction of cardiovascu- in a mouse inner medullary collecting duct NAs (miRNA) in circadian rhythmicity. lar events and effects of chronotherapy: Ra- cell line. Am J Physiol 285: F664–F673, J Genet 87: 505–511, 2008 tionale and design of the MAPEC study. 2003 79. Nagel R, Clijsters L, Agami R: The miRNA- Chronobiol Int 24: 749–775, 2007 68. Gumz ML, Stow LR, Lynch IJ, Greenlee MM, 192/194 cluster regulates the Period gene 54. Hermida RC, Ayala DE, Fernández JR: Influ- Rudin A, Cain BD, Weaver DR, Wingo CS: family and the circadian clock. FEBS J 276: ence of circadian time of hypertension treat- The circadian clock protein Period 1 regu- 5447–5455, 2009 ment on cardiovascular risk: results of the lates expression of the renal epithelial so- 80. Silva CM, Sato S, Margolis RN: No time to MAPEC study. Chronobiology Int 8: 1629– dium channel in mice. J Clin Invest 119: lose: Workshop on circadian rhythms and 1651, 2010 2423–2434, 2009 metabolic disease. Genes Dev 24: 1456– 55. Koch BC, Nagtegaal JE, Hagen EC, Wee 69. Saifur Rohman M, Emoto N, Nonaka H, 1464, 2010

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