MAGED2 Enhances Expression and Function of NCC at the Cell Surface via cAMP Signaling Under Hypoxia

• Published in: Cells (Basel, Switzerland) Switzerland), 2025-01, Vol.14 (3), p.175
• Main Authors: Radi, Aline, Nasrah, Sadiq, Auer, Michelle, Renigunta, Aparna, Weber, Stefanie, Seaayfan, Elie, Kömhoff, Martin
• Format: Article
• Language: English
• Subjects: Adenylate cyclase; Amniotic fluid; Animals; Antibodies; Bartter syndrome; Bartter's syndrome; Birth; Cell Hypoxia; Cell Membrane - metabolism; Cell surface; Cyclic AMP; Cyclic AMP - metabolism; Endocytosis; Exocytosis; Forskolin; HEK293 Cells; Humans; Hypertension; Hypoxia; Kidneys; Kinases; Localization; Lysosomes; Lysosomes - metabolism; MAGED2; Membrane trafficking; Mutagenesis; Mutation; NCC; Plasmids; Potassium; protein trafficking; Proteins; Renal function; Salt; Signal Transduction; Sodium; Therapeutic targets; Ubiquitination
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells14030175

Mutations in cause transient antenatal Bartter syndrome (tBS) characterized by excessive amounts of amniotic fluid due to impaired renal salt transport via and NCC, high perinatal mortality, and pre-term birth. Surprisingly, renal salt handling completely normalizes after birth. Previously, we demonstrated that, under hypoxic conditions, depletion enhances endocytosis of GalphaS (Gαs), reducing adenylate cyclase (AC) activation and cAMP production. This impaired cAMP signaling likely contributes to the dysfunction of salt transporters and NCC, explaining salt wasting and the subsequent recovery with renal oxygenation after birth. In this study, we show that depletion significantly decreases both total cellular and plasma membrane NCC expression and activity. We further demonstrate that 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 -depleted cells. Conversely, overexpression increases NCC expression and membrane localization, although this effect is diminished in Gαs-depleted cells, indicating that Gαs acts downstream of . In summary, our findings reveal the essential role of 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.