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The Circadian Clock in the Kidney

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The Circadian Clock in the Kidney BRIEF REVIEW www.jasn.org 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 598 ISSN : 1046-6673/2204-598 J Am Soc Nephrol 22: 598–604, 2011 www.jasn.org BRIEF REVIEW 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
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