Molecular clock is involved in predictive circadian adjustment of renal function

Abstract

Renal excretion of water and major electrolytes exhibits a significant circadian rhythm. This functional periodicity is believed to result, at least in part, from circadian changes in secretion/reabsorption capacities of the distal nephron and collecting ducts. Here, we studied the molecular mechanisms underlying circadian rhythms in the distal nephron segments, i.e., distal convoluted tubule (DCT) and connecting tubule (CNT) and the cortical collecting duct (CCD). Temporal expression analysis performed on microdissected mouse DCT/CNT or CCD revealed a marked circadian rhythmicity in the expression of a large number of genes crucially involved in various homeostatic functions of the kidney. This analysis also revealed that both DCT/CNT and CCD possess an intrinsic circadian timing system characterized by robust oscillations in the expression of circadian core clock genes (clock, bma11, npas2, per, cry, nr1d1) and clock-controlled Par bZip transcriptional factors dbp, hlf, and tef. The clock knockout mice or mice devoid of dbp/hlf/tef (triple knockout) exhibit significant changes in renal expression of several key regulators of water or sodium balance (vasopressin V2 receptor, aquaporin-2, aquaporin-4, ␣ENaC). Functionally, the loss of clock leads to a complex phenotype characterized by partial diabetes insipidus, dysregulation of sodium excretion rhythms, and a significant decrease in blood pressure. Collectively, this study uncovers a major role of molecular clock in renal function.circadian rhythm ͉ homeostasis ͉ renal function R ecent evidence suggests that many if not all specific physiological functions are under the control of the circadian timing system. The mammalian circadian timing system is a hierarchically organized network of molecular oscillators driven by a central pacemaker located in the suprachiasmatic nucleus (SCN) of hypothalamus. This central pacemaker functions in a self-sustained fashion, but is reset each day by exposure to environmental synchronizers, mainly the light/dark cycle. The SCN masterclock drives the rest-activity cycle, which in turn imposes the feeding pattern [reviewed in (1, 2)]. The feeding time seems to be the dominant cue for circadian rhythms in the peripheral tissues (3, 4). Central and peripheral oscillators share a similar molecular core clock based on a set of self-autonomous transcriptional/ translational feedback loops. The key molecular components of these loops are the PAS domain transcriptional factors CLOCK, BMAL1, and NPAS2 and the feedback repressors PER1, PER2, CRY1, and CRY2. The orphan nuclear receptors NR1D1 and, probably, NR1D2 form an accessory feedback loop. The core oscillators confer circadian rhythmicity on a set of output genes underlying the tissue-specific functional rhythms. Current estimates indicate that up to 10% of the cellular transcriptome may follow a circadian expression pattern (5-7). Several recent studies have also demonstrated that the transcription of only a minority of these circadian genes is driven by systemic humoral or neurona...

Immunometabolism: Is it under the eye of the clock?

“…• 30% increased weight gain on high fat diet [80] • Increased susceptibility to sepsis with LPS or Listeria [22,65] • Greater IL-6, TNF␣ [22] • Lower IL-10 [22] Clock Global • Partial diabetes [160] • Reduced NF-B activation in MEFs and BMDMs. [66,116] Clock 19 Global • Obese and display impaired glucose sensitivity with insulin resistance and reduced islet size [112,113] • Increased plasma triglyceride and glucose levels [85,114] • Increased fibrotic damage in model of pulmonary fibrosis [87] • Impaired anti-oxidant defense [87] Cry1/Cry2 Global • Increased NAD+ and ATP.…”

The Circadian Clock Modulates Renal Sodium Handling

“…In mice, suppression or decrease of the circadian clock activity via deletion of the circadian transcriptional activators Bmal1, Clock, or Npas2 leads to low BP, whereas its constitutive activation via deletion of the circadian repressors Cry1 and Cry2 results in salt-sensitive hypertension. [1][2][3][4] Wang et al have recently shown that mice simultaneously devoid of three prolineand acidic amino acid-rich basic leucine zipper circadian transcriptional factors Dbp, Hlf, and Tef exhibit a significant reduction in BP. 5 Maintaining BP within the normal range strongly depends on the capacity of the kidney to precisely regulate sodium content in the extracellular space.…”

Tick Tock

“…Interestingly, the overall phenotype of the kidney-specific Bmal1 KO is very similar to that of the global KO of CLOCK 12,14 and that of Per1. 8,13,15 The features of these phenotypes include reduced plasma aldosterone, mild polyuria, altered urinary sodium excretion, and reduced BP.…”

“…Similar relationships between systolic BP and a J-shaped relationship for diastolic BP have been demonstrated in patients receiving maintenance hemodialysis, as well as in patients with less advanced CKD who do not require dialysis. 12,13 In the absence of aortic valve insufficiency, the pattern of high systolic BP, low diastolic BP, and increased pulse pressure are a marker of vascular stiffness. This has been extensively studied in CKD and ESRD, and it reflects accelerated arteriosclerosis and vascular calcification in progressive renal disease.…”

“…8,9 Consistent with these mechanistic molecular findings in renal models, studies in circadian KO mice have consistently demonstrated a role for each of the core clock proteins in BP control. [10][11][12][13] An important role for the kidney in these BP phenotypes has often been proposed, but the lack of renal cell type-specific KO models of circadian genes has prevented the use of a genetic model to directly test this hypothesis.…”