한빛사 논문
Jae Wook Lee1, 4, 5, Mohammad Alsady2, 5, Chung-Lin Chou1, 5, Theun de Groot2, Peter M.T. Deen2, Mark A. Knepper1, 6, Carolyn M. Ecelbarger1, 3, 6,*
1 Epithelial Systems Biology Laboratory, Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
2 Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands
3 Division of Endocrinology and Metabolism, Department of Medicine, Georgetown University, Washington, District of Columbia, USA
4 Nephrology Clinic, National Cancer Center, Goyang, Gyeonggi-do, South Korea
5 These authors contributed equally.
6 These authors contributed equally.
*Correspondence: Carolyn M. Ecelbarger, Department of Medicine, Georgetown University, Washington, District of Columbia, 20057, USA.
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 : aquaporin-2, cell cycle, cortical collecting duct, TGFβ, transcriptome
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