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.
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.
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.
Albano G (2017), Increased bone resorption by osteoclast-specific deletion of the sodium/calcium exchanger isoform 1 (NCX1), in Pflugers Archives
Wnuk M (2017), Neuropilin1 regulates glomerular function and basement membrane composition through pericytes in the mouse kidney, in Kidney International
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.
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.
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
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.
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.
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.
Zhang J (2014), Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit, in Am J Physiol Renal Physiol
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.