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Sci Rep. 2015 Dec 17;5:18311. doi: 10.1038/srep18311.

Autophagic degradation of aquaporin-2 is an early event in hypokalemia-induced nephrogenic diabetes insipidus.

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Department of Pediatrics, Faculty of Medicine, Thammasat University Klong Luang, Pathumthani, 12120, Thailand.
Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University Bangkok, 10700, Thailand.
Systems Biology Center, Research Affairs, Faculty of Medicine, Chulalongkorn University 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand.
Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University Bangkok, 10700, Thailand.
National Institute of Diabetes and Digestive and Kidney, Bethesda MD 20892, United States.
Department of Electrical &Computer Engineering and Department of Computer Science, Western Michigan University Kalamazoo, 49008, United States.
Department of Chemistry, National Cheng Kung University, Tainan City, 701, Taiwan.
Department of Biomedicine and Center for Interactions of Proteins in Epithelial Transport, Aarhus University, Aarhus, 8000, Denmark.
Epithelial Systems Biology Laboratory, National Heart, Lung, and Blood Institute, Bethesda MD 20892, United States.


Hypokalemia (low serum potassium level) is a common electrolyte imbalance that can cause a defect in urinary concentrating ability, i.e., nephrogenic diabetes insipidus (NDI), but the molecular mechanism is unknown. We employed proteomic analysis of inner medullary collecting ducts (IMCD) from rats fed with a potassium-free diet for 1 day. IMCD protein quantification was performed by mass spectrometry using a label-free methodology. A total of 131 proteins, including the water channel AQP2, exhibited significant changes in abundance, most of which were decreased. Bioinformatic analysis revealed that many of the down-regulated proteins were associated with the biological processes of generation of precursor metabolites and energy, actin cytoskeleton organization, and cell-cell adhesion. Targeted LC-MS/MS and immunoblotting studies further confirmed the down regulation of 18 selected proteins. Electron microscopy showed autophagosomes/autophagolysosomes in the IMCD cells of rats deprived of potassium for only 1 day. An increased number of autophagosomes was also confirmed by immunofluorescence, demonstrating co-localization of LC3 and Lamp1 with AQP2 and several other down-regulated proteins in IMCD cells. AQP2 was also detected in autophagosomes in IMCD cells of potassium-deprived rats by immunogold electron microscopy. Thus, enhanced autophagic degradation of proteins, most notably including AQP2, is an early event in hypokalemia-induced NDI.

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