{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:38:41Z","timestamp":1777595921423,"version":"3.51.4"},"reference-count":55,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Behring R\u00f6ntgen Foundation","award":["67-0060"],"award-info":[{"award-number":["67-0060"]}]},{"name":"Behring R\u00f6ntgen Foundation","award":["67-0061"],"award-info":[{"award-number":["67-0061"]}]},{"name":"Philipps-Universit\u00e4t Marburg","award":["67-0060"],"award-info":[{"award-number":["67-0060"]}]},{"name":"Philipps-Universit\u00e4t Marburg","award":["67-0061"],"award-info":[{"award-number":["67-0061"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mutations in MAGED2 cause transient antenatal Bartter syndrome (tBS) characterized by excessive amounts of amniotic fluid due to impaired renal salt transport via NKCC2 and NCC, high perinatal mortality, and pre-term birth. Surprisingly, renal salt handling completely normalizes after birth. Previously, we demonstrated that, under hypoxic conditions, MAGED2 depletion enhances endocytosis of GalphaS (G\u03b1s), reducing adenylate cyclase (AC) activation and cAMP production. This impaired cAMP signaling likely contributes to the dysfunction of salt transporters NKCC2 and NCC, explaining salt wasting and the subsequent recovery with renal oxygenation after birth. In this study, we show that MAGED2 depletion significantly decreases both total cellular and plasma membrane NCC expression and activity. We further demonstrate that MAGED2 depletion disrupts NCC trafficking by reducing exocytosis, increasing endocytosis, and promoting lysosomal degradation via enhanced ubiquitination. Additionally, forskolin (FSK), which increases cAMP production by activating AC, rescues NCC expression and localization in MAGED2-depleted cells. Conversely, MAGED2 overexpression increases NCC expression and membrane localization, although this effect is diminished in G\u03b1s-depleted cells, indicating that G\u03b1s acts downstream of MAGED2. In summary, our findings reveal the essential role of MAGED2 in regulating NCC function and trafficking under hypoxic conditions, providing new insights into the mechanisms behind salt loss in tBS and identifying potential therapeutic targets.<\/jats:p>","DOI":"10.3390\/cells14030175","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T12:24:09Z","timestamp":1737635049000},"page":"175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["MAGED2 Enhances Expression and Function of NCC at the Cell Surface via cAMP Signaling Under Hypoxia"],"prefix":"10.3390","volume":"14","author":[{"given":"Aline","family":"Radi","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University Hospital Giessen and Marburg, Philipps University Marburg, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sadiq","family":"Nasrah","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Hospital Giessen and Marburg, Philipps University Marburg, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Auer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Hospital Giessen and Marburg, Philipps University Marburg, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aparna","family":"Renigunta","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Hospital Giessen and Marburg, Philipps University Marburg, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9498-2337","authenticated-orcid":false,"given":"Stefanie","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Hospital Giessen and Marburg, Philipps University Marburg, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4839-9834","authenticated-orcid":false,"given":"Elie","family":"Seaayfan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Hospital Giessen and Marburg, Philipps University Marburg, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6499-5313","authenticated-orcid":false,"given":"Martin","family":"K\u00f6mhoff","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Hospital Giessen and Marburg, Philipps University Marburg, 35043 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1097\/00041552-200309000-00008","article-title":"Bartter syndrome","volume":"12","author":"Hebert","year":"2003","journal-title":"Curr. 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