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Kidney Int. 2018 Jan;93(1):128-146. doi: 10.1016/j.kint.2017.06.008. Epub 2017 Aug 23.

Single-tubule RNA-Seq uncovers signaling mechanisms that defend against hyponatremia in SIADH.

Author information

1
Epithelial Systems Biology Laboratory, Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA; Nephrology Clinic, National Cancer Center, Goyang, Gyeonggi-do, South Korea.
2
Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
3
Epithelial Systems Biology Laboratory, Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
4
Epithelial Systems Biology Laboratory, Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA; Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington, District of Columbia, USA. Electronic address: ecelbarc@georgetown.edu.

Abstract

In the syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyponatremia is limited by onset of vasopressin-escape caused by loss of the water channel aquaporin-2 in the renal collecting duct despite high circulating vasopressin. Here, we use the methods of systems biology in a well-established rat model of SIADH to identify signaling pathways activated at the onset of vasopressin-escape. Using single-tubule RNA-Seq, full transcriptomes were determined in microdissected cortical collecting ducts of vasopressin-treated rats at 1, 2, and 4 days after initiation of oral water loading in comparison to time-control rats without water loading. The time-dependent mRNA abundance changes were mapped to gene sets associated with curated canonical signaling pathways and revealed evidence of perturbation of transforming growth factor β signaling and epithelial-to-mesenchymal transition on Day 1 of water loading simultaneous with the initial fall in Aqp2 gene expression. On Day 2 of water loading, transcriptomic changes mapped to Notch signaling and the transition from G0 into the cell cycle but arrest at the G2/M stage. There was no evidence of cell proliferation or altered principal or intercalated cell numbers. Exposure of vasopressin-treated cultured mpkCCD cells to transforming growth factor β resulted in a virtually complete loss of aquaporin-2. Thus, there is a partial epithelial-to-mesenchymal transition during vasopressin escape with a subsequent shift from quiescence into the cell cycle with eventual arrest and loss of aquaporin-2.

KEYWORDS:

TGFβ; aquaporin-2; cell cycle; cortical collecting duct; transcriptome

PMID:
28843412
PMCID:
PMC5750119
DOI:
10.1016/j.kint.2017.06.008
[Indexed for MEDLINE]
Free PMC Article

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