Unknown,Transcriptomics,Genomics,Proteomics

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Role of TBC1D4 in mouse kidneys: Identification of compensatory mechanisms in the DCT of TBC1D4-deficient mice

ABSTRACT: In vitro studies identified TBC1D4 as an regulator of renal ion and water transporting proteins. However, TBC1D4-deficient mice did not show a defective renal salt and water homeostasis. With microarray analysis we aimed to decipher compensatory mechanisms in TBC1D4-deficient mice which might mask the renal phenotype already on transciptomic levels. We used and compared mRNA of COPAS-sorted and -enriched distal convoluted tubule (DCT)-cells, known to express TBC1D4 at high levels, of 8-week old male homogenous C57/Bl6 mice of TBC1D4-deficient and wild-type mice.

ORGANISM(S): Mus musculus

SUBMITTER: Marianna Di Chiara

PROVIDER: E-GEOD-67701 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description: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, M-oM-^AM-!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. Experiment Overall Design: We examined the temporal profiles of gene expression in mouse distal nephron segments and collecting ducts. The RNA was extracted from microdissected distal convoluted tubules and connecting tubules (DCT/CNT samples) or, cortical collecting ducts (CCD samples). Animals were sacrificed for microdissection every 4 hours, i.e. at ZT0, ZT4, ZT8, ZT12, ZT16 and ZT20 (ZT M-bM-^@M-^S Zeitgeber (circadian) time, indicates time of light-on as ZT0 and time of light-off as ZT12). The microarray hybridization was performed in duplicates on two pools of RNA composed of equivalent amounts of RNA prepared from five animals at each ZT time-point.

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Role of TBC1D4 in mouse kidneys: Identification of compensatory mechanisms in the DCT of TBC1D4-deficient mice

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