Exploration des fonctions tubulaires rénales

Encyclopédie médico-chirurgicale. Néphrologie, Journal Year: 2025, Volume and Issue: 37(1), P. 1 - 19

Published: Jan. 1, 2025

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

Cells, Journal Year: 2025, Volume and Issue: 14(3), P. 175 - 175

Published: Jan. 23, 2025

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, pre-term birth. Surprisingly, handling completely normalizes after Previously, we demonstrated that, under hypoxic conditions, depletion enhances endocytosis GalphaS (Gαs), reducing adenylate cyclase (AC) activation cAMP production. This signaling likely contributes the dysfunction transporters explaining wasting subsequent recovery with oxygenation In this study, show that significantly decreases both total cellular plasma membrane NCC expression activity. We further demonstrate disrupts trafficking exocytosis, increasing endocytosis, promoting lysosomal degradation enhanced ubiquitination. Additionally, forskolin (FSK), which increases production activating AC, rescues localization MAGED2-depleted cells. Conversely, overexpression localization, although effect is diminished Gαs-depleted cells, indicating Gαs acts downstream MAGED2. summary, our findings reveal essential role regulating function providing new insights into mechanisms behind loss tBS identifying potential therapeutic targets.

Language: Английский

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MAGED2 Depletion Promotes Stress-Induced Autophagy by Impairing the cAMP/PKA Pathway

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(17), P. 13433 - 13433

Published: Aug. 30, 2023

Melanoma-associated antigen D2 (MAGED2) plays an essential role in activating the cAMP/PKA pathway under hypoxic conditions, which is crucial for stimulating renal salt reabsorption and thus explaining transient variant of Bartter's syndrome. The also known to regulate autophagy, a lysosomal degradation process induced by cellular stress. Previous studies showed that two members melanoma-associated antigens MAGE-family inhibit autophagy. To explore potential MAGED2 stress-induced specific MAGED2-siRNA were used HEK293 cells physical hypoxia oxidative stress (cobalt chloride, mimetic). Depletion resulted reduced p62 levels upregulation both autophagy-related genes (ATG5 ATG12) as well autophagosome marker LC3II compared control siRNA. increase autophagy markers MAGED2-depleted was further confirmed leupeptin-based assay concurred with highest accumulation. Likewise, hypoxia, immunofluorescence HEK293, HeLa U2OS cell lines demonstrated pronounced accumulation LC3B puncta upon depletion. Moreover, absent human fetal kidneys but markedly expressed kidney from MAGED2-deficient subject. Induction suggests potentially general conditions. Various other stressors (brefeldin A, tunicamycin, 2-deoxy-D-glucose, camptothecin) analyzed, all absence MAGED2. Forskolin (FSK) inhibited, whereas GNAS Knockdown hypoxia. In contrast MAGE proteins, has inhibitory on only Hence, prominent regulation conditions evident, may contribute impaired promoting salt-transporters patients mutation.

Language: Английский

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Reciprocal Regulation of MAGED2 and HIF-1α Augments Their Expression under Hypoxia: Role of cAMP and PKA Type II

Cells, Journal Year: 2022, Volume and Issue: 11(21), P. 3424 - 3424

Published: Oct. 29, 2022

Hypoxia stabilizes the transcription factor HIF-1α, which promotes of many genes essential to adapt reduced oxygen levels. Besides proline hydroxylation, expression HIF-1α is also regulated by a range other posttranslational modifications including phosphorylation cAMP-dependent protein kinase A (PKA), HIF-1α. We recently demonstrated that MAGED2 required for cAMP generation under hypoxia and proposed this regulation may explain transient nature antenatal Bartter syndrome (aBS) due mutations. Consequently, we sought determine whether hypoxic induction requires MAGED2. In HEK293 HeLa cells, knock-down impaired maximal physical as evidenced time-course experiments, showed signification reduction upon depletion. Similarly, using cobalt chloride induce depletion its appropriate induction. Given known effect cAMP/PKA pathway on rescue with isoproterenol forskolin acting upstream downstream Gαs, respectively. Importantly, while induced above control levels in MAGED2-depleted had no effect. To further delineate PKA subtype involved, analyzed two inhibitors identified type II regulates Interestingly, mRNA were increased mimetic. Moreover, Thus, our data provide evidence reciprocal hypoxia, revealing therefore new regulatory mechanism aBS caused

Language: Английский

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Identification of a novel intronic mutation of MAGED2 gene in a Chinese family with antenatal Bartter syndrome

BMC Medical Genomics, Journal Year: 2024, Volume and Issue: 17(1)

Published: Jan. 18, 2024

Abstract Background Antenatal Bartter syndrome is a life-threatening disease caused by mutation in the MAGED2 gene located on chromosome Xp11. It characterized severe polyhydramnios and extreme prematurity. While most reported mutations are exon region, variations intron region rarely reported. Methods In our study, we employed whole exome sequencing Sanger to genotype members of this family. Additionally, minigene assay was conducted evaluate impact genetic variants splicing. Results Our findings reveal novel intronic variant (NM_177433.3:c.1271 + 4_1271 7delAGTA) 10 gene. Further analysis using demonstrated that activated an cryptic splice site, resulting 96 bp insertion mature mRNA. Conclusions results indicate (c.1271 pathogenic. This expands spectrum highlights significance sequence analysis.

Language: Английский

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Case Report: Transient antenatal bartter syndrome in an extremely preterm infant with a novel MAGED2 variant

Frontiers in Pediatrics, Journal Year: 2023, Volume and Issue: 10

Published: Feb. 2, 2023

Variants in the MAGED2 may cause antenatal transient Bartter syndrome, which is characterised by polyhydramnios, preterm labour, postnatal polyuria, hypokalaemia and metabolic alkalosis. Transient gross hematuria acute kidney injury such cases have not been reported previously. The patient, a boy, was born at gestational age of 27 + 5 weeks. Polyhydramnios has detected 24 weeks gestation. Polyuria, hyponatraemia, hypokalaemia, weight loss, occur after birth. urinary ultrasonography showed no abnormality, month treatment with liquid electrolytes nutritional management, clinical symptoms improved. Whole-exome sequencing revealed variant : c.1426C > T, p.Arg476X, inherited from mother, who healthy. During 1-year follow-up, child grew developed normal renal function electrolyte levels. This first report syndrome caused China an extremely infant exhibited previously unreported symptoms: injury. newly found expands spectrum genetic variants associated syndrome; it can be early testing overmedication, thereby avoided.

Language: Английский

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Successful antenatal treatment of MAGED2‐related Bartter syndrome and review of treatment options and efficacy

Prenatal Diagnosis, Journal Year: 2023, Volume and Issue: 44(2), P. 172 - 179

Published: Dec. 30, 2023

Abstract A new form of transient antenatal Bartter syndrome (aBS) was recently identified that is associated with the X ‐linked MAGED2 variant. Case reports demonstrate this variant leads to severe polyhydramnios may result in preterm birth or pregnancy loss. There limited but promising evidence amnioreductions improve fetal outcomes rare condition. We report a woman two affected pregnancies. In first pregnancy, patient diagnosed mild‐to‐moderate second trimester ultimately resulted labor and delivery at 25 weeks demise. Whole exome sequencing amniotic fluid sample after loss revealed c.1337G>A considered diagnostically. The subsequent confirmed by chorionic villi sampling also be managed frequent ultrasounds three spontaneous vaginal 37 6 days viable newborn no overt electrolyte abnormalities suggesting complete resolution. detailed review published cases ‐related aBS provided. Our focuses on individuals who received treatment. total 31 unique MAGED2‐ related were compiled. Amnioreduction performed 23 18 amnioreduction performed. average gestational age significantly lower without serial (28.7 vs. 30.71 weeks, p = 0.03). Neonatal mortality seen 5/18 amnioreduction, observed amnioreduction. identifiable cause, whole should considered. Intensive ultrasound surveillance recommended for management aBS.

Language: Английский

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Protein Quality Control of NKCC2 in Bartter Syndrome and Blood Pressure Regulation

Cells, Journal Year: 2024, Volume and Issue: 13(10), P. 818 - 818

Published: May 10, 2024

Mutations in NKCC2 generate antenatal Bartter syndrome type 1 (type BS), a life-threatening salt-losing nephropathy characterized by arterial hypotension, as well electrolyte abnormalities. In contrast to the genetic inactivation of NKCC2, inappropriate increased activity has been associated with salt-sensitive hypertension. Given importance hypertension and pathophysiology prenatal BS, studying molecular regulation this Na-K-2Cl cotransporter attracted great interest. Therefore, several studies have addressed various aspects regulation, such phosphorylation post-Golgi trafficking. However, at pre-Golgi level remained unknown for years. Similar transmembrane proteins, export from ER appears be rate-limiting step cotransporter’s maturation trafficking plasma membrane. The most compelling evidence comes patients 5 severe form whom is not detectable apical membrane thick ascending limb (TAL) cells due retention ER-associated degradation (ERAD) mechanisms. addition, BS one diseases linked ERAD pathways. recent years, determinants protein quality control identified. aim review therefore summarize data regarding discuss their potential implications blood pressure regulation.

Language: Английский

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Update on NKCC2 regulation in the thick ascending limb (TAL) by membrane trafficking, phosphorylation, and protein-protein interactions

Frontiers in Physiology, Journal Year: 2024, Volume and Issue: 15

Published: Dec. 9, 2024

The thick ascending limb (TAL) of loop Henle is essential for NaCl, calcium and magnesium homeostasis, pH balance urine concentration. NKCC2 the main transporter NaCl reabsorption in TAL its regulation very complex. There have been recent advancements toward understanding how regulated by protein trafficking, protein-protein interaction, phosphorylation/dephosphorylation. Here, we update latest molecular mechanisms players that control function, which gives an increasingly complex picture NKKC2 apical membrane TAL.

Language: Английский

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A Case of a Novel MAGED2 Mutation Resulting in Non-transient Bartter’s Syndrome in an Adult Female

Cureus, Journal Year: 2023, Volume and Issue: unknown

Published: May 7, 2023

Bartter’s syndrome (BS) is a disorder caused by group of rare mutations that result in defective salt reabsorption the thick ascending loop Henle. BS characterized wasting, hypokalemia, and metabolic alkalosis, among other abnormalities. A MAGE-D2 mutation results an X-linked form BS. It transient antenatal presentation observed to completely resolve early infancy, usually occurring males. We present case adult female with intermittent recurrence symptoms derangements consistent She also has family history polyhydramnios renal disease. Genetic testing later confirmed novel mutation. Her atypical emphasizes heterogenous different raises possibility persistence abnormalities beyond infancy gene.

Language: Английский

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