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Physiological role of the sodium/hydrogen exchanger NHE6

English title Physiological role of the sodium/hydrogen exchanger NHE6
Applicant Fuster Daniel Guido
Number 152829
Funding scheme Project funding
Research institution Respiratory Medicine Department Universitätsklinik Inselspital
Institution of higher education University of Berne - BE
Main discipline Pathophysiology
Start/End 01.05.2014 - 30.04.2017
Approved amount 372'000.00
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All Disciplines (7)

Discipline
Pathophysiology
Molecular Biology
Cellular Biology, Cytology
Biochemistry
Biophysics
Endocrinology
Physiology : other topics

Keywords (1)

Membrane transport, sodium/hydrogen exchanger

Lay Summary (German)

Lead
NHE6 ist ein Natrium/Protonen Austauscher der auf intrazellulären Membranen in Endosomen vorkommt. Ueber die physiologische Funktion dieses Membrantransporters ist zur Zeit wenig bekannt. Ziel dieses Projektes ist es, dies zu ändern.
Lay summary

Natrium/Protonen Austauscher (NHEs) sind ubiquitäre, im ganzen Pflanzen- und Tierreich vorkommende Membrantransportproteine. Wie es der Name sagt, tauschen diese Proteine Natrium gegen Protonen aus. Dies führt zu einer Anhäufung von Protonen auf der einen und Natrium auf der anderen Membranseite. 13 NHE Isoformen sind aktuell bei Säugetieren bekannt. NHE1 bis NHE5 kommen primär auf der Zelloberfläche vor, NHE6 bis NHE9 sind in der Membran von intrazellulären Organellen. Daneben gibt es einen Spermien-spezifischen NHE und zwei erst kürzlich entdeckte NHE Isoformen, NHA1 und NHA2.

Endosomen sind Transportvesikel in der Zelle, die essentiell sind für die Aufnahme von Substanzen und Flüssigkeiten in die Zelle. NHE3, NHE6, NHE9 und NHA2 kommen alle in diesen Endosomen vor. Seltene Erbgutveränderungen im NHE6 Gen führen beim Menschen zu Ablagerung von Abbauprodukten im Hirn mit geistiger Behinderung und Epilepsie.  NHE6 kommt auch in vielen anderen Organen ausserhalb des Zentralnervensystems vor, aber die Funktion von NHE6 in diesen Organen ist zur Zeit nicht bekannt. Ebenso unklar ist zum aktuellen Zeitpunkt, warum die Säugetierzelle mehrere NHEs in den Endosomen braucht.

Unser Projekt hat zum Ziel, die physiologische Funktion von NHE6 ausserhalb des Zentralnervensystems zu erforschen und die Frage zu klären, warum Säugetierzellen mehrere endosomale NHEs benötigen. Durch das Studium der endosomalen NHE Isoformen versprechen wir uns Erkenntnisse die für die Therapie und /oder Diagnostik von menschliche Erkrankungen wichtig sind. Dies betrifft Erkrankungen wie Bluthochdruck, Diabetes oder Knochenschwund.

Direct link to Lay Summary Last update: 26.03.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)
Pathare Ganesh, Anderegg Manuel, Albano Giuseppe, Lang Florian, Fuster Daniel G. (2018), Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC), in Scientific Reports, 8(1), 3590-3590.
Changes in V-ATPase subunits of human urinary exosomes reflect the renal response to acute acid/alkali loading and the defects in distal renal tubular acidosis
Pathare Ganesh, Dhayat Nasser A., Mohebbi Nilufar, Wagner Carsten A., Bobulescu Ion A., Moe Orson W., Fuster Daniel G. (2018), Changes in V-ATPase subunits of human urinary exosomes reflect the renal response to acute acid/alkali loading and the defects in distal renal tubular acidosis, in Kidney International, 93(4), 871-880.
Acute regulated expression of pendrin in human urinary exosomes
Pathare Ganesh, Dhayat Nasser, Mohebbi Nilufar, Wagner Carsten A., Cheval Lydie, Neuhaus Thomas J., Fuster Daniel G. (2018), Acute regulated expression of pendrin in human urinary exosomes, in Pflügers Archiv - European Journal of Physiology, 470(2), 427-438.
Increased bone resorption by osteoclast-specific deletion of the sodium/calcium exchanger isoform 1 (NCX1)
Albano G (2017), Increased bone resorption by osteoclast-specific deletion of the sodium/calcium exchanger isoform 1 (NCX1), in Pflugers Archives, 225-233.
Neuropilin1 regulates glomerular function and basement membrane composition through pericytes in the mouse kidney
Wnuk M (2017), Neuropilin1 regulates glomerular function and basement membrane composition through pericytes in the mouse kidney, in Kidney International, 868-879.
Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function
Dhayat Nasser A., Ackermann Daniel, Pruijm Menno, Ponte Belen, Ehret Georg, Guessous Idris, Leichtle Alexander Benedikt, Paccaud Fred, Mohaupt Markus, Fiedler Georg-Martin, Devuyst Olivier, Pechère-Bertschi Antoinette, Burnier Michel, Martin Pierre-Yves, Bochud Murielle, Vogt Bruno, Fuster Daniel G. (2016), Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function, in Kidney International, 90(3), 648-657.
Loss of Sodium/Hydrogen Exchanger NHA2 Exacerbates Obesity- and Aging-Induced Glucose Intolerance in Mice
Deisl Christine, Anderegg Manuel, Albano Giuseppe, Lüscher Benjamin P., Cerny David, Soria Rodrigo, Bouillet Elisa, Rimoldi Stefano, Scherrer Urs, Fuster Daniel G. (2016), Loss of Sodium/Hydrogen Exchanger NHA2 Exacerbates Obesity- and Aging-Induced Glucose Intolerance in Mice, in PLOS ONE, 11(9), e0163568-e0163568.
Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement
Gambaro Giovanni, Croppi Emanuele, Coe Fredric, Lingeman James, Moe Orson, Worcester Elen, Buchholz Noor, Bushinsky David, Curhan Gary C., Ferraro Pietro Manuel, Fuster Daniel, Goldfarb David S., Heilberg Ita Pfeferman, Hess Bernard, Lieske John, Marangella Martino, Milliner Dawn, Preminger Glen M., Reis Santos Jose’ Manuel, Sakhaee Khashayar, Sarica Kemal, Siener Roswitha, Strazzullo Pasquale, Williams James C. (2016), Metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations: a consensus statement, in J Nephrol, 1.
Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria
Dhayat N., Simonin A., Anderegg M., Pathare G., Lu scher B. P., Deisl C., Albano G., Mordasini D., Hediger M. A., Surbek D. V., Vogt B., Sass J. O., Kloeckener-Gruissem B., Fuster D. G. (2016), Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria, in Journal of the American Society of Nephrology, 27(5), 1426-1436.
The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers
Dhayat N. A., Schaller A., Albano G., Poindexter J., Griffith C., Pasch A., Gallati S., Vogt B., Moe O. W., Fuster D. G. (2016), The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers, in Journal of the American Society of Nephrology, 27(5), 1544-1554.
Sodium-Dependent Phosphate Transporters in Osteoclast Differentiation and Function
Albano Giuseppe, Moor Matthias, Dolder Silvia, Siegrist Mark, Wagner Carsten A., Biber Jürg, Hernando Nati, Hofstetter Willy, Bonny Olivier, Fuster Daniel G. (2015), Sodium-Dependent Phosphate Transporters in Osteoclast Differentiation and Function, in PLOS ONE, 10(4), e0125104-e0125104.
Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit
Zhang J (2014), Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit, in Am J Physiol Renal Physiol, F1063-F1071.

Collaboration

Group / person Country
Types of collaboration
Prof. Johannes Loffing, Anatomisches Institut, Universität Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Bernard Thorens, Center for integrative Genomics, Universität Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Donald Hilgemann, UT Southwestern Medical Center, Dallas, TX United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Willy Hofstetter, Departement für klinische Forschung, Universität Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting of the American Society of Nephrology Talk given at a conference Phosphate transport by bone cells 15.11.2016 Chicago, United States of America Fuster Daniel Guido;
Annual Meeting of the American Society of Nephrology Talk given at a conference The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K associated with impaired urinary acidification in recurrent stone formers 03.11.2015 San Diego, United States of America Fuster Daniel Guido;
Consensus Conference for the metabolic diagnosis and medical prevention of calcium nephrolithiasis and its systemic manifestations Individual talk Distal Renal Tubular Acidosis and Nephrolithiasis 26.03.2015 Rom, Italy Fuster Daniel Guido;
Membrane Transport Proteins Individual talk Physiological Role of the Sodium/Hydrogen Exchanger NHA2 13.07.2014 Vermont, United States of America Fuster Daniel Guido; Deisl Christine;
Physiological function of the sodium/hydrogen exchanger NHA2 Individual talk Physiological function of the sodium/hydrogen exchanger NHA2 01.05.2014 Frankfurt, Germany Fuster Daniel Guido;


Associated projects

Number Title Start Funding scheme
172974 Mechanisms of thiazide-induced glucose intolerance 01.05.2017 Project funding
135503 Sodium/hydrogen exchanger NHA2 - quest for biological function 01.05.2011 Project funding
135503 Sodium/hydrogen exchanger NHA2 - quest for biological function 01.05.2011 Project funding
66227 Mechanisms of regulation of proximal tubular sodium reabsorption in the kidney. 01.08.2001 Fellowships for prospective researchers
117732 Elucidation of the pathways leading to inactivation and degradation of the sodium / hydrogen exchanger isoform 1 (NHE1) 01.01.2008 Project funding

Abstract

Na+/H+ exchangers (NHEs) are ubiquitous ion transporters present in lipid bilayers in simple prokaryotes and eukaryotes which harness the electrochemical gradient of one ion to energize the uphill transport of the other. In mammals, 13 NHE isoforms have been cloned so far, including the mostly plasmalemmal NHE1-5, intracellular NHE6-9, a sperm specific plasmalemmal NHE and two recently cloned evolutionarily very conserved NHEs, named NHA1 and NHA2. Of the 13 NHE isoforms known thus far NHA2, NHE3, NHE6 and NHE9 were shown to localize to endosomes. Due to technical challenges in the study of intracellular transporters as well as lack of mutant mice until recently, endosomal NHEs remain poorly understood. We recently demonstrated that the endosomal NHE NHA2 is critical for clathrin-mediated endocytosis and insulin secretion in ß-cells. In the case of NHE6, mutations in humans were shown to be the cause of a neurological syndrome characterized by intellectual disability, microcephaly, epilepsy, ataxia and behavioural abnormalities. Loss of NHE6 in mice leads to an endolysosomal storage disease with similarities to clinical and anatomical abnormalities observed in humans. NHE6 is also highly expressed in many cell types outside the brain, but the physiological role of the transporter in non-neuronal tissues has not been studied, neither in humans nor in mice.The overall goal of our proposal is to decipher the physiological role of endosomal NHE6 in the kidney, bone and endocrine pancreas. Based on our preliminary data and published evidence we hypothesize that endosomal NHE6 plays an important role in insulin secretion, renal distal tubular electrolyte handling as well as bone homeostasis. We plan to rigorously test our hypothesis by in-depth study of NHE6 mutant mice and complementary in vitro studies. We also aim at deciphering the individual functions of NHEs in the mammalian endosome and their exact role during the endocytotic process. In this proposal we will focus on the interplay between endosomal NHEs NHE6 and NHA2, the two NHEs known to be involved in clathrin-mediated endocytosis. This will be achieved by the study of NHE6 single and NHE6/NHA2 double knock-out mice and cells. Furthermore, our recent discovery of high level expression of functional NHE6 on the plasma membrane of osteoclasts offers a unique and unprecedented opportunity to gain insights into NHE6 transport mechanisms. We plan to study in detail NHE6 transport kinetics and inhibitor sensitivities by use of fluorometry- as well as electrophysiology-based approaches in osteoclasts.As evidenced by our preliminary data and published work, NHE6 is a highly promising membrane protein. The study of NHE6 will undoubtedly lead to important discoveries with relevance to human physiology and disease. Research on the role of NHE6 in kidney, pancreas and bone will likely shed light on the pathogenesis of arterial hypertension, diabetes mellitus and osteoporosis, diseases, which pose a major burden to our society. I strongly believe that the approach of combining in vivo and in vitro studies, as proposed, is the only way to definitively establish the physiological role of NHE6. Given our promising preliminary data, our longstanding experience in the study of NHEs and the expert environment at the Institute of Biochemistry and Molecular Medicine and the Division of Nephrology, Hypertension and Clinical Pharmacology at the University of Bern, I am convinced that this proposal has a high chance of success.
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