title: Glutathionylation of the aquaporin-2 water channel: a novel post-translational modification modulated by the oxidative stress.
abstract: Aquaporin-2 (AQP2) is the vasopressin-regulated water channel that controls renal water reabsorption and urine concentration. AQP2 undergoes different regulated post-translational modifications, including phosphorylation and ubiquitylation, which are fundamental for controlling AQP2 cellular localization, stability, and function. The relationship between AQP2 and S-glutathionylation is of potential interest because reactive oxygen species (ROS), produced under renal failure or nephrotoxic drugs, may influence renal function as well as the expression and the activity of different transporters and channels, including aquaporins. Here, we show for the first time that AQP2 is subjected to S-glutathionylation in kidney and in HEK-293 cells stably expressing AQP2. S-Glutathionylation is a redox-dependent post-translational modification controlling several signal transduction pathways and displaying an acute effect on free cytosolic calcium concentration. Interestingly, we found that in fresh kidney slices, the increased AQP2 S-glutathionylation correlated with tert-butyl hydroperoxide-induced ROS generation. Moreover, we also found that cells expressing wild-type human calcium-sensing receptor (hCaSR-wt) and its gain of function (hCaSR-R990G; hCaSR-N124K) had a significant decrease in AQP2 S-glutathionylation secondary to reduced ROS levels and reduced basal intracellular calcium concentration compared with mock cells. Together, these new findings provide fundamental insight into cell biological aspects of AQP2 function and may be relevant to better understand and explain pathological states characterized by an oxidative stress and AQP2-dependent water reabsorption disturbs.
authors.affiliation: From the Department Biosciences Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy, the Istituto Nazionale di Biostrutture e Biosistemi, 00136 Roma, Italy, and grazia.tamma@uniba.it.
authors.forename: Grazia
authors.initials: G
authors.lastname: Tamma
authors.affiliation: From the Department Biosciences Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Ranieri
authors.affiliation: From the Department Biosciences Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: Di Mise
authors.affiliation: From the Department Biosciences Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Centrone
authors.affiliation: From the Department Biosciences Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy, the Istituto Nazionale di Biostrutture e Biosistemi, 00136 Roma, Italy, and the Centro di Eccellenza di Genomica in Campo Biomedico ed Agrario, Università degli Studi di Bari Aldo Moro, 70121 Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Svelto
authors.affiliation: From the Department Biosciences Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy, the Istituto Nazionale di Biostrutture e Biosistemi, 00136 Roma, Italy, and the Centro di Eccellenza di Genomica in Campo Biomedico ed Agrario, Università degli Studi di Bari Aldo Moro, 70121 Bari, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Valenti
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D014867:Water / Q000378:metabolism*
chemical_list: C496023:AQP2 protein, human; C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D017382:Reactive Oxygen Species; D014867:Water; D005978:Glutathione
keywords: AQP2; Aquaporin; CaSR; Glutathionylation; Kidney; Oxidative Stress; Post-translational Modification (PTM); Water Reabsorption
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