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To discover mechanisms of AQP2 loss, previous investigators have carried out either transcriptomics (lithium\u2010induced NDI, unilateral ureteral obstruction, endotoxin\u2010induced NDI) or proteomics (hypokalaemia\u2010associated NDI, hypercalcaemia\u2010associated NDI, bilateral ureteral obstruction), yielding contrasting views. Here, to address whether there may be common mechanisms underlying loss of AQP2 in acquired NDI disorders, we have used bioinformatic data integration techniques to combine information from all transcriptomic and proteomic data sets. The analysis reveals roles for autophagy\/apoptosis, oxidative stress and inflammatory signalling as key elements of the mechanism that results in loss of AQP2. These processes can cause AQP2 loss through the combined effects of repression of <jats:italic>Aqp2<\/jats:italic> gene transcription, generalized translational repression, and increased autophagic degradation of proteins including AQP2. Two possible types of stress\u2010sensor proteins, namely death receptors and stress\u2010sensitive protein kinases of the EIF2AK family, are discussed as potential triggers for signalling processes that result in loss of AQP2.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15564-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Prior studies have shown in a variety of animal models of acquired nephrogenic diabetes insipidus (NDI) that loss of the aquaporin\u20102 (AQP2) protein is a common feature.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Investigations of acquired NDI using transcriptomics (RNA\u2010seq) and proteomics (protein mass spectrometry) have led to differing conclusions regarding mechanisms of AQP2 loss.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Bioinformatic integration of transcriptomic and proteomic data from these prior studies now reveals that acquired NDI models map to three core processes: oxidative stress, apoptosis\/autophagy and inflammatory signalling.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These processes cause loss of AQP2 through translational repression, accelerated degradation of proteins, and transcriptional repression.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp284634","type":"journal-article","created":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T06:25:05Z","timestamp":1682663105000},"page":"3191-3206","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["\u2018Aquaporin\u2010omics\u2019: mechanisms of aquaporin\u20102 loss in polyuric disorders"],"prefix":"10.1113","volume":"602","author":[{"given":"Angela","family":"Mak","sequence":"first","affiliation":[{"name":"Epithelial Systems Biology Laboratory, Systems Biology Center, National Heart, Lung, and Blood Institute National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih\u2010Chien","family":"Sung","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Tri\u2010Service General Hospital National Defense Medical Center  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trairak","family":"Pisitkun","sequence":"additional","affiliation":[{"name":"Epithelial Systems Biology Laboratory, Systems Biology Center, National Heart, Lung, and Blood Institute National Institutes of Health  Bethesda MD USA"},{"name":"Center of Excellence in Systems Biology, Faculty of Medicine Chulalongkorn University  Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sookkasem","family":"Khositseth","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Faculty of Medicine Thammasat University  Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2276-8091","authenticated-orcid":false,"given":"Mark A.","family":"Knepper","sequence":"additional","affiliation":[{"name":"Epithelial Systems Biology Laboratory, Systems Biology Center, National Heart, Lung, and Blood Institute National Institutes of Health  Bethesda MD 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