Marc Lombès

The PremUp Foundation, Lutetia Parisorum, Île-de-France, France

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Publications (178)695.21 Total impact

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    ABSTRACT: Aldosterone regulates sodium homeostasis by activating the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily. Hyperaldosteronism leads to deleterious effects on the kidney, blood vessels and heart. Although steroidal antagonists such as spironolactone and eplerenone are clinically useful for the treatment of cardiovascular diseases, they are associated with several side effects. Finerenone, a novel non-steroidal MR antagonist is presently being evaluated in two clinical phase IIb trials. Here, we characterized the molecular mechanisms of action of finerenone and spironolactone at several key steps of the MR signaling pathway. Molecular modeling and mutagenesis approaches allowed identifying Ser810 and Ala773 as key residues for the high MR selectivity of finerenone. Moreover, we showed that, in contrast to spironolactone, which activates the S810L mutant MR responsible for a severe form of early-onset hypertension, finerenone displays strict antagonistic properties. Aldosterone-dependent phosphorylation and degradation of MR are inhibited by both finerenone and spironolactone. However, automated quantification of MR subcellular distribution demonstrated that finerenone delays aldosterone-induced nuclear accumulation of MR more efficiently than spironolactone. Finally, chromatin immunoprecipitation assays revealed that, as opposed to spironolactone, finerenone inhibits MR, Steroid-Receptor-Coactivator-1 (SRC-1) and RNA polymerase II binding at the regulatory sequence of the SCNN1A gene and also remarkably reduces basal MR and SRC-1 recruitment, unraveling a specific and unrecognized inactivating mechanism on MR signaling. Overall, our data demonstrate that the highly potent and selective MR antagonist finerenone specifically impairs several critical steps of the MR signaling pathway, and therefore represents a promising new generation MR antagonist. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 07/2015; DOI:10.1074/jbc.M115.657957 · 4.57 Impact Factor
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    ABSTRACT: Mitotane (o,p'-DDD), the only approved drug for advanced adrenocortical carcinoma (ACC), is a lipophilic agent that accumulates into circulating lipoprotein fractions and high lipid-containing tissues. The aim of our study was to evaluate the in vivo and in vitro biological implication of serum lipoproteins on pharmacological action of mitotane. Distribution and concentration of mitotane were studied in plasma and adrenal tissue samples from mitotane-treated patients. The impact of lipoprotein-bound or free (LP-F) mitotane was analyzed on proliferation and apoptosis of human adrenocortical H295R cells. A retrospective study of ACC patients treated or not with statins was also performed. o,p'-DDD distribution among VLDL, LDL, HDL and lipoprotein-free (LP-F) fractions obtained after ultracentrifugation of 23 plasmas of mitotane-treated patients was widely distributed in each subfraction. A positive correlation was observed between mitotane levels in plasma and in LDL, HDL but also LP-F compartment. Intra-tumor o,p'-DDD concentrations in 5 ACC samples of mitotane-treated patients were found independent of cholesterol transporter expression, scavenger receptors (SrB1) and LDL-Receptors. In vitro studies showed significant higher anti-proliferative and pro-apoptotic effects and higher cell and mitochondrial uptake of mitotane when H295R cells were grown in LP-F medium. Finally, retrospective study of an ACC cohort of 26 mitotane-treated patients revealed that statin therapy was significantly associated with a higher rate of tumor control. Altogether, our in vitro and in vivo studies provided compelling evidence for a greater efficacy of lipoprotein-free mitotane. ACC patients may thus benefit from therapeutic strategies that aim to increase LP-F mitotane fraction.
    The Journal of Clinical Endocrinology and Metabolism 06/2015; DOI:10.1210/JC.2015-2080 · 6.31 Impact Factor
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    ABSTRACT: Aldosterone exerts its effects mainly by activating the mineralocorticoid receptor (MR), a transcription factor that regulates gene expression through complex and dynamic interactions with coregulators and transcriptional machinery, leading to fine-tuned control of vectorial ionic transport in the distal nephron. To identify genome-wide aldosterone-regulated MR targets in human renal cells, we set up a chromatin immunoprecipitation (ChIP) assay by using a specific anti-MR antibody in a differentiated human renal cell line expressing green fluorescent protein (GFP)-MR. This approach, coupled with high-throughput sequencing, allowed identification of 974 genomic MR targets. Computational analysis identified an MR response element (MRE) including single or multiple half-sites and palindromic motifs in which the AGtACAgxatGTtCt sequence was the most prevalent motif. Most genomic MR-binding sites (MBSs) are located >10 kb from the transcriptional start sites of target genes (84%). Specific aldosterone-induced recruitment of MR on the first most relevant genomic sequences was further validated by ChIP-quantitative (q)PCR and correlated with concomitant and positive aldosterone-activated transcriptional regulation of the corresponding gene, as assayed by RT-qPCR. It was notable that most MBSs lacked MREs but harbored DNA recognition motifs for other transcription factors (FOX, EGR1, AP1, PAX5) suggesting functional interaction. This work provides new insights into aldosterone MR-mediated renal signaling and opens relevant perspectives for mineralocorticoid-related pathophysiology.-Le Billan, F., Khan, J. A., Lamribet, K., Viengchareun, S., Bouligand, J., Fagart, J., Lombès, M. Cistrome of the aldosterone-activated mineralocorticoid receptor in human renal cells. © FASEB.
    The FASEB Journal 06/2015; DOI:10.1096/fj.15-274266 · 5.48 Impact Factor
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    ABSTRACT: Salsalate improves glucose intolerance and dyslipidemia in type 2 diabetes patients, but the mechanism is still unknown. The aim of the present study was to unravel the molecular mechanisms involved in these beneficial metabolic effects of salsalate by treating mice with salsalate during and after development of high fat diet-induced obesity. We found that salsalate attenuated and reversed high fat diet-induced weight gain, in particular fat mass accumulation, improved glucose tolerance and lowered plasma triglyceride (TG) levels. Mechanistically, salsalate selectively promoted the uptake of fatty acids from glycerol tri[(3)H]oleate-labeled lipoprotein-like emulsion particles by brown adipose tissue (BAT), decreased the intracellular lipid content in BAT and increased rectal temperature, all pointing to more active BAT. Treatment of differentiated T37i brown adipocytes with salsalate increased uncoupled respiration in cells. Moreover, salsalate upregulated Ucp1 expression and enhanced glycerol release, a dual effect that was abolished by inhibition of protein kinase A (PKA). In conclusion, salsalate activates BAT, presumably by directly activating brown adipocytes via the PKA pathway, suggesting a novel mechanism that may explain its beneficial metabolic effects in type 2 diabetes patients. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 12/2014; 64(5). DOI:10.2337/db14-1125 · 8.47 Impact Factor
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    ABSTRACT: Menière's disease, clinically characterized by fluctuating, recurrent, and invalidating vertigo, hearing loss, and tinnitus, is linked to an increase in endolymph volume, the so-called endolymphatic hydrops. Since dysregulation of water transport could account for the generation of this hydrops, we investigated the role of aquaporin 3 (AQP3) in water transport into endolymph, the K-rich, hyperosmotic fluid that bathes the apical ciliated membrane of sensory cells, and we studied the regulatory effect of dexamethasone upon AQP3 expression and water fluxes. The different AQP subtypes were identified in inner ear by RT-PCR. AQP3 was localized in human utricle and mouse inner ear by immunohistochemistry and confocal microscopy. Unidirectional transepithelial water fluxes were studied by means of (3)H2O transport in murine EC5v vestibular cells cultured on filters, treated or not with dexamethasone (10(-7) M). The stimulatory effect of dexamethasone upon AQP3 expression was assessed in EC5v cells and in vivo in mice. AQP3 was unambiguously detected in human utricle and was highly expressed in both endolymph secretory structures of the mouse inner ear, and EC5v cells. We demonstrated that water reabsorption, from the apical (endolymphatic) to the basolateral (perilymphatic) compartments, was stimulated by dexamethasone in EC5v cells. This was accompanied by a glucocorticoid-dependent increase in AQP3 expression at both messenger RNA (mRNA) and protein level, presumably through glucocorticoid receptor-mediated AQP3 transcriptional activation. We show that glucocorticoids enhance AQP3 expression in human inner ear and stimulate endolymphatic water reabsorption. These findings should encourage further clinical trials evaluating glucocorticoids efficacy in Menière's disease.
    Pflügers Archiv - European Journal of Physiology 10/2014; DOI:10.1007/s00424-014-1629-5 · 3.07 Impact Factor
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    M Hage, M Lombès, P Chanson
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    ABSTRACT: This review focuses on new aspects in craniopharyngiomas with emphasis on pathogenic mechanisms and treatment strategies that were presented at the joined Endocrine Society/International Society of Endocrinology meeting in Chicago in June 2014. Craniopharyngiomas are benign epithelial tumors arising from the pituitary stalk or gland. Two subtypes could be distinguished: an adamatinomatous form that is more common in children, and a papillary form that is observed almost exclusively in adults. Besides these histological differences, these two variants differ in some molecular features that have been recently identified and could have important therapeutic implications. Despite its histologically benign nature, the morbidities related to the tumor itself or its treatment raise many concerns and excess mortality rates up to nine times higher than in the general population has been reported. Among the potential sequelae of craniopharyngiomas, obesity seems the most frequent. The difficulty in the management of this obesity lies in its complex underlying pathophysiological mechanisms. Complete resection of localized tumors should be attempted while a limited hypothalamus-sparing surgery followed or not by radiotherapy should be adopted in tumors involving the hypothalamus. A multidisciplinary approach including, in particular, a dedicated neurosurgeon, and a therapeutic strategy tailored to the individual presentation of the craniopharyngioma in any patient should be initiated at diagnosis for improving the prognosis of these tumors. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
  • Françoise Borson-Chazot, Marc Lombès
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    ABSTRACT: Background: Tubular immaturity, responsible for sodium wasting, is critical during the neonatal period, particularly in preterm neonates. This relates to partial renal aldosterone resistance (Martinerie, Ped Res 2009), coincident with low tubular expression of the mineralocorticoid receptor in newborns (Martinerie, Endocrinology 2009). Objective and methods: Our clinical trial (NCT01176162) aimed to assess aldosterone resistance in neonates according to gestational age and during a 1-year postnatal follow-up period, by measuring urinary aldosterone concentration (UAC) and its correlation to the urinary Na/K ratio as an index of renal aldosterone sensitivity. Results: We enrolled 170 newborns prospectively, classified into three groups: <33 GW (gestational weeks) (52 patients), 33–36 GW (69 patients), >37 GW (49 patients). Plasma aldosterone levels measured from umbilical cord blood samples were very high in the >37 GW group (1001±98 pg/ml) and decreased significantly with gestational age (583±48 and 380±55 pg/ml in the 33–36 and <33 GW groups, respectively, P<0.0001). This was associated with an increase in renin levels (from 81±10 pg/ml in the >37 GW group to 135±22 pg/ml in the <33 GW group), suggesting an aldosterone biosynthesis/secretion defect in preterms. UAC followed a similar pattern (from 20.2±3.2 g/mmol urinary creatinine in term neonates to 8.8±1.2 in preterms, P<0.0001) significantly correlated with plasma aldosterone levels in all groups (P<0.0001), demonstrating its accuracy as a non-invasive index of aldosterone secretion. Renal aldosterone resistance was demonstrated in all groups given the lack of correlation between UAC and the urinary Na/K ratio, and high sodium wasting at birth in very preterm infants. Renal aldosterone responsiveness appears in term infants at 1 month of age (P=0.02) while renal aldosterone insensitivity persists in the preterm groups beyond 3 months. Conclusion: These results uncover the mechanism of sodium wasting in preterm neonates and underscore new potential therapeutic management based on UAC measurement.
    ESPE, Dublin; 09/2014
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    ABSTRACT: The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The molecular mechanism by which CB1R blockade reverses dyslipidemia in obesity has not yet been clarified. In this study, we showed that CB1R blockade with the systemic CB1R blocker rimonabant enhanced whole-body energy expenditure and activated brown adipose tissue (BAT), indicated by increased expression of genes involved in BAT thermogenesis and decreased lipid droplet size in BAT. This was accompanied by selectively increased triglyceride (TG) uptake by BAT and lower plasma TG levels. Interestingly, the effects on BAT activation were still present at thermoneutrality and could be recapitulated by using the strictly peripheral CB1R antagonist AM6545, indicating direct peripheral activation of BAT. Indeed, CB1R blockade directly activated T37i brown adipocytes, resulting in enhanced uncoupled respiration, most likely via enhancing cAMP/PKA signaling via the adrenergic receptor pathway. Our data indicate that selective targeting of the peripheral CB1R in BAT has therapeutic potential in attenuating dyslipidemia and obesity.-Boon, M. R., Kooijman, S., van Dam, A. D., Pelgrom, L. R., Berbée, J. F. P., Visseren, C. A. R., van Aggele, R. C., van den Hoek, A. M., Sips, H. C. M., Lombès, M., Havekes, L. M., Tamsma, J. T., Guigas, B., Meijer, O. C., Jukema, J. W., Rensen, P. C. N. Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity.
    The FASEB Journal 08/2014; DOI:10.1096/fj.13-247643 · 5.48 Impact Factor
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    ABSTRACT: Brown adipose tissue (BAT) and brown-like cells in white adipose tissue (WAT) can dissipate energy through thermogenesis, a process mediated by uncoupling protein 1 (UCP1). We investigated whether stress hormones ACTH and corticosterone contribute to BAT activation and browning of WAT. ACTH and corticosterone were studied in male mice exposed to 4 or 23°C for 24 h. Direct effects were studied in T37i mouse brown adipocytes and primary cultured murine BAT and inguinal WAT (iWAT) cells. In vivo effects were studied using (18)F-deoxyglucose positron emission tomography. Cold exposure doubled serum ACTH concentrations (P=0.03) and fecal corticosterone excretion (P=0.008). In T37i cells, ACTH dose-dependently increased Ucp1 mRNA (EC50=1.8 nM) but also induced Ucp1 protein content 88% (P=0.02), glycerol release 32% (P=0.03) and uncoupled respiration 40% (P=0.003). In cultured BAT and iWAT, ACTH elevated Ucp1 mRNA by 3-fold (P=0.03) and 3.7-fold (P=0.01), respectively. In T37i cells, corticosterone prevented induction of Ucp1 mRNA and Ucp1 protein by both ACTH and norepinephrine in a glucocorticoid receptor (GR)-dependent fashion. ACTH and GR antagonist RU486 independently doubled BAT (18)F-deoxyglucose uptake (P=0.0003 and P=0.004, respectively) in vivo. Our results show that ACTH activates BAT and browning of WAT while corticosterone counteracts this.-Van den Beukel, J. C., Grefhorst, A., Quarta, C., Steenbergen, J., Mastroberardino, P. G., Lombès, M., Delhanty, P. J., Mazza, R., Pagotto, U., van der Lely, A. J., Themmen, A. P. N. Direct activating effects of adrenocorticotropic hormone (ACTH) on brown adipose tissue are attenuated by corticosterone.
    The FASEB Journal 08/2014; 28(11). DOI:10.1096/fj.14-254839 · 5.48 Impact Factor
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    ABSTRACT: Glucocorticoid Receptor (GR), a ubiquitous transcriptional factor, regulates target gene expression upon activation by glucocorticoids, notably cortisol, a corticosteroid hormone synthesized in the adrenal cortex. We thus hypothesized that both GR and cortisol might be involved in the regulation of adrenal physiology and steroidogenesis in an autocrine manner. In a cortisol-secreting human adrenocortical cell line (H295R), GR-dependent signaling pathway was pharmacologically modulated either by dexamethasone (DEX), a GR agonist or by RU486, a GR antagonist or was knocked-down by small interfering RNA strategy (SiRNA). We showed that GR activation, elicited by 48 h exposure to DEX, exerts a global positive regulatory effect on adrenal steroidogenesis as revealed by a 1.5- to 2-fold increase in cortisol, 11-deoxycortisol and 17-hydroxyprogesterone secretion associated with a significant enhanced expression of steroidogenesis factors such as StAR, CYP11A1, CYP21A2 and CYP11B1. In sharp contrast, RU486 treatment exerted opposite effects by decreasing both steroid production and expression of these steroidogenic factors. Likewise, GR repression by SiRNA also significantly reduced StAR, CYP11A1, and CYP11B1 mRNA levels. Interestingly, RU486 resulted in a significant CYP21A2 enzymatic blockade as demonstrated by a massive increase in 17-hydroxyprogesterone concentrations in RU486-treated H295R cell supernatants while cortisol and 11-deoxycortisol secretions were reduced by more than 60%. Consistently, we also demonstrated that metabolic conversion of 17-hydroxyprogesterone into 11-deoxycortisol onto H295R cells was drastically blunted in the presence of RU 486. Finally, steady state levels of MC2R transcripts encoding for ACTH receptor were significantly induced by DEX, unlikely through a direct GR-mediated transcriptional activation as opposed to CYP11A1 and FKBP5 target genes. These results could account for a higher glucocorticoid-elicited ACTH sensitivity of adrenocortical cells. Our study identifies a positive ultra-short regulatory loop exerted by GR on steroidogenesis in H295R cells, thus supporting a complex intra-adrenal GR-mediated feedback, likely relevant for human adrenocortical pathologies.
    Molecular and Cellular Endocrinology 07/2014; DOI:10.1016/j.mce.2014.07.012 · 4.24 Impact Factor
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    ABSTRACT: Mitotane (o,p'DDD) is the most effective treatment of advanced adrenocortical carcinoma (ACC) but its mechanism of action remains unknown. Previous studies suggested that o,p'DDA may represent the active metabolite of mitotane. We aimed at reevaluating the potential role and pharmacological effects of o,p'DDA. Functional consequences of o,p'DDA exposure were studied on proliferation, steroidogenesis, and mitochondrial respiratory chain in human H295R and SW13 adrenocortical cells. Mitotane and its metabolites were quantified using high-performance liquid chromatography combined to an ultraviolet detection in these cells treated with o,p'DDD or o,p'DDA and in human adrenal tissues. Dose-response curves up to 300 μM showed that, as opposed to o,p'DDD, o,p'DDA did not inhibit cell proliferation nor alter respiratory chain complex IV activity, gene expression nor induce mitochondrial biogenesis, oxidative stress, or apoptosis. However, whereas mitotane drastically decreased expression of genes involved in steroidogenesis, o,p'DDA slightly reduced expression of some steroidogenic enzymes and exerts weak anti-secretory effects only at high doses. While o,p'DDD concentration was significantly reduced by 40 % in H295R cell supernatants after 48 h incubation, o,p'DDA levels remained unchanged suggesting that o,p'DDA was not efficiently transported into the cells. o,p'DDA was not detected in cell homogenates or supernatants after 48 h exposure to o,p'DDD, consistent with the absence of o,p'DDA production in these models. Finally, unlike o'p'DDD, we found that o,p'DDA content was undetectable in two ACC and one normal adrenal gland of mitotane-treated patients, suggesting a lack of cellular uptake and in situ production. Our results demonstrate that o,p'DDD, but not o,p'DDA, induces functional alterations in adrenal cells.
    07/2014; 5(5). DOI:10.1007/s12672-014-0189-7
  • Damien Le Menuet, Marc Lombès
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    ABSTRACT: Mineralocorticoid receptor (MR), a hormone-activated transcription factor belonging to the nuclear receptor superfamily, exerts widespread actions in many tissues such as tight epithelia, the cardiovascular system, adipose tissues and macrophages. In the mammalian brain, MR is present in the limbic areas where it is highly expressed in neurons of the hippocampus and mostly absent in other regions while the glucocorticoid receptor (GR) expression is ubiquitous. MR binds both aldosterone and glucocorticoids, the latter having a ten-fold higher affinity for MR than for the closely related GR. However, owing to the minimal aldosterone transfer across the blood brain barrier and the absence of neuronal 11β hydroxysteroid dehydrogenase type 2 as an intracellular gate-keeper, neuronal MR appears to be fully occupied even at low physiological glucocorticoid levels while GR activation only occurs at high glucocorticoid concentrations, i.e. at the peak of the circadian rhythm or under stress. This defined a one hormone/two receptors system that works in balance, modulating a large spectrum of actions in the central nervous system. MR and GR are involved in the stress responses, the regulation of neuron excitability, long term potentiation, neuroprotection and neurogenesis in the dentate gyrus. MR thus constitutes a key factor in the arising of higher cognitive functions such as memorization, learning and mood. This review presents an overview of various roles of MR in the central nervous system which are somewhat less studied than that of GR, in the light of recent data obtained using cellular models, animal models and clinical investigations.
    Steroids 06/2014; 91. DOI:10.1016/j.steroids.2014.05.018 · 2.72 Impact Factor
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    ABSTRACT: The neonatal period is characterized in humans by a tubular immaturity responsible for sodium wasting, notably in preterm neonates. We have previously demonstrated a partial renal aldosterone resistance coincident with low tubular expression of the mineralocorticoid receptor in term newborns (1, 2). The objective of our clinical trial (NCT01176162) was to assess aldosterone resistance in neonates according to gestational age and during a one-year postnatal follow-up period, by measuring urinary aldosterone concentration (UAC) and its correlation to the urinary Na/K ratio as an index of renal aldosterone sensitivity. One hundred and seventy newborns were enrolled prospectively, classified into 3 gestational age groups: <33 GW (gestational weeks) (52 patients), 33-36 GW (69 patients), >37 GW (49 patients). Plasma aldosterone levels measured from umbilical cord blood samples were very high in the >37 GW group (1001±98 pg/ml). However, these levels significantly decreased with gestational age (583±48 and 380±55 pg/ml in the 33-36 and <33 GW groups, respectively, p<0.0001). This was associated with an increase in renin levels (from 81±10 pg/ml in the >37 GW group to 135±22 pg/ml in the <33 GW group) suggesting an aldosterone biosynthesis/secretion defect in preterms. UAC followed a similar pattern (from 20.2±3.2 mg/mmol urinary creatinine in term neonates to 8.8±1.2 in preterms, p<0.0001), significantly correlated with plasma aldosterone levels in all groups (p<0.0001), demonstrating its reliability as an accurate and non-invasive index of aldosterone secretion. Renal aldosterone resistance was demonstrated in newborns given the lack of correlation between UAC and the urinary Na/K ratio in all groups, and high sodium wasting at birth in very preterm infants (Na/creatinine urinary ratio: 75.7, 46.0 and 10.7 in the <33 GW, 33-36 GW and >37 GW group, respectively). During follow-up, UAC progressively decreased to reach adult levels at one year of age in term infants, while in the <33 GW group, UAC increased till one month reaching values of term newborns at birth, with a delayed diminution afterwards. Renal aldosterone responsiveness appears in term infants at one month of age (p=0.02) while renal aldosterone insensitivity persists in the preterm groups beyond 3 months of follow-up. These results uncover the mechanism of sodium wasting in preterm neonates and underscore new potential therapeutic management of sodium homeostasis based on UAC measurement. 1- Martinerie et al., Ped Research 2009; 66: 323-328 2- Martinerie et al., Endocrinology 2009; 150: 4414-4424
    ICE/ENDO, Chicago; 06/2014

Publication Stats

4k Citations
695.21 Total Impact Points

Institutions

  • 2011–2014
    • The PremUp Foundation
      Lutetia Parisorum, Île-de-France, France
  • 2009–2014
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
    • Senri Kinran University
      Ibaragi, Ōsaka, Japan
  • 2006–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • Baylor College of Medicine
      • Department of Molecular & Cellular Biology
      Houston, Texas, United States
  • 1984–2014
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2010
    • Hôpital Armand-Trousseau (Hôpitaux Universitaires Est Parisien)
      Lutetia Parisorum, Île-de-France, France
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 1989–1990
    • Columbia University
      • Department of Microbiology and Immunology
      New York City, NY, United States