Search

Your search keyword '"Matthias T. Wolf"' showing total 5 results
Start Over Author "Matthias T. Wolf"
5 results on '"Matthias T. Wolf"'

1. Insulin receptor substrate 4 deficiency mediates the insulin effect on the epithelial magnesium channel TRPM6 and causes hypomagnesemia

Author

Jing Zhang, Sung Wan An, Sudha Neelam, Anuja Bhatta, Mingzhu Nie, Claudia Duran, Manjot Bal, Femke Latta, Jianghui Hou, Joseph J. Otto, Julia Kozlitina, Andrew Lemoff, Joost Hoenderop, Michel Baum, and Matthias T Wolf

Abstract

The kidney is the key regulator of magnesium (Mg2+) homeostasis in the human body. In the distal convoluted tubule (DCT), the apical epithelial magnesium (Mg2+) channel TRPM6, determines how much Mg2+ is excreted in the urine. To better understand the regulation of human renal Mg2+ absorption we identified novel, potential interaction partners of TRPM6 by pursuing a liquid chromatography – tandem mass spectrometry (LC-MS/MS) proteomics approach.We found insulin receptor substrate 4 (IRS4) enriched with TRPM6 tagged to glutathione S-transferase (TRPM6-GST) but not GST control. Physical interaction between IRS4 and TRPM6 was confirmed by co-immunoprecipitation. Applying microdissection of mouse tubules, we detected Irs4 mRNA expression mostly in the DCT and to a lower degree in the proximal tubule and thick ascending limb of Henle. Given the overall low abundance of Irs4 mRNA along the tubule we investigated the phenotype of Irs4 knockout mice (Irs4-/-). These Irs4-/- mice displayed significantly higher urinary and fecal Mg2+ losses and lower blood Mg2+ levels than wild-type (WT) mice. Claudin-16, claudin-19, and Hnf1b mRNA and Claudin-16 and Trpm6 protein expression was significantly higher in kidneys of 3 month old Irs4-/- mice consistent with a compensatory mechanism to conserve Mg2+. Applying whole-cell patch-clamp recording we confirmed the stimulatory role of insulin on TRPM6 channel activity and showed that IRS4 targets the two TRPM6 phosphorylation sites T1391 and S1583 to enhance TRPM6 current density. To test the effect of Mg2+ deficiency on metabolism, we performed glucose and insulin tolerance studies, which were mildly abnormal in Irs4-/- mice.SIGNIFICANCE STATEMENTMagnesium (Mg2+) is the second most abundant intracellular cation but the regulation of Mg2+ homeostasis is not well understood. The kidney is the key organ for regulating Mg2+ homeostasis. Insulin is a known stimulator of the apical epithelial Mg2+channel TRPM6. We present a novel modifier of Mg2+ absorption with insulin receptor substrate 4 (IRS4) which illuminates further, how insulin activates the TRPM6 channel and modifies Mg2+ homeostasis. Applying protein biochemistry, tubular microdissection, whole mouse physiology, and patch-clamp recording, we demonstrate that IRS4 mediates the stimulatory effect of insulin by enhancing phosphorylation of two specific TRPM6 residues. Irs4-/- mice develop increased urinary and stool Mg2+ losses, lower serum Mg2+ concentration, and display mild impairment in glucose and insulin tolerance.

Published
2022
Full Text
View/download PDF

3. Gentamicin Inhibits Ca(2+) Channel TRPV5 and Induces Calciuresis Independent of the Calcium-Sensing Receptor-Claudin-14 Pathway

Author

Wouter H. van Megen, Megan R. Beggs, Sung-Wan An, Patrícia G. Ferreira, Justin J. Lee, Matthias T. Wolf, R. Todd Alexander, and Henrik Dimke

Subjects
kidney tubule, calcium-sensing receptor, TRPV Cation Channels, General Medicine, gentamicin, Mice, Basic Research, HEK293 Cells, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Nephrology, Claudins, Animals, Humans, Calcium, Calcium Channels, Rabbits, Gentamicins, Carrier Proteins, Receptors, Calcium-Sensing, hypercalciuria
Abstract

Contains fulltext : 249144.pdf (Publisher’s version ) (Closed access) BACKGROUND: Treatment with the aminoglycoside antibiotic gentamicin can be associated with severe adverse effects, including renal Ca(2+) wasting. The underlying mechanism is unknown but it has been proposed to involve activation of the Ca(2+)-sensing receptor (CaSR) in the thick ascending limb, which would increase expression of claudin-14 (CLDN14) and limit Ca(2+) reabsorption. However, no direct evidence for this hypothesis has been presented. METHODS: We studied the effect of gentamicin in vivo using mouse models with impaired Ca(2+) reabsorption in the proximal tubule and the thick ascending limb. We used a Cldn14 promoter luciferase reporter assay to study CaSR activation and investigated the effect of gentamicin on activity of the distal nephron Ca(2+) channel transient receptor potential vanilloid 5 (TRPV5), as determined by patch clamp in HEK293 cells. RESULTS: Gentamicin increased urinary Ca(2+) excretion in wild-type mice after acute and chronic administration. This calciuretic effect was unaltered in mice with genetic CaSR overactivation and was present in furosemide-treated animals, whereas the calciuretic effect in Cldn14(-/-) mice and mice with impaired proximal tubular Ca(2+) reabsorption (claudin-2 [CLDN2]-deficient Cldn2(-/-) mice) was equivalent to that of wild-type mice. In vitro, gentamicin failed to activate the CaSR. In contrast, patch clamp analysis revealed that gentamicin strongly inhibited rabbit and human TRPV5 activity and chronic gentamicin administration downregulated distal nephron Ca(2+) transporters. CONCLUSIONS: Gentamicin does not cause hypercalciuria via activation of the CaSR-CLDN14 pathway or by interfering with proximal tubular CLDN2-dependent Ca(2+) reabsorption. Instead, gentamicin blocks distal Ca(2+) reabsorption by direct inhibition of the Ca(2+) channel TRPV5. These findings offer new insights into Ca(2+) wasting in patients treated with gentamicin.

Published
2022
Full Text
View/download PDF

4. Contributors

Author

Soraya Abbasi, James Abbey, N. Scott Adzick, Sun-Young Ahn, Kurt H. Albertine, Karel Allegaert, Seth L. Alper, Gabriel Altit, Steven M. Altschuler, Ruben E. Alvaro, Jennifer M.H. Amorosa, Kelsey L. Anbuhl, Claus Yding Andersen, Richard A. Anderson, David J. Askenazi, Richard Lambert Auten, Julie Autmizguine, Timur Azhibekov, Stephen A. Back, Jérôme Badaut, Peter Russell Baker, Philip L. Ballard, Eduardo H. Bancalari, Tatiana Barichello, Frederick Battaglia, Michel Baum, Simon Beggs, Edward F. Bell, Corinne Benchimol, Manon J.N.L. Benders, Laura Bennet, Phillip R. Bennett, Melvin Berger, Wolfgang Bernhard, John F. Bertram, Vikrant K. Bhosle, Vinod K. Bhutani, M. Jane Black, Joseph M. Bliss, David L. Bolender, Joline E. Brandenburg, Delma L. Broussard, Laura Davidson Brown, Douglas G. Burrin, Barbara Cannon, Michael Caplan, Susan E. Carlson, David P. Carlton, Georgina Caruana, William J. Cashore, Piya Chaemsaithong, Noppadol Chaiyasit, Jennifer R. Charlton, Carol L. Cheatham, Sylvain Chemtob, Yi-Yung Chen, Robert L. Chevalier, Sadhana Chheda, Andrew J. Childs, Robert D. Christensen, Alison Chu, David H. Chu, Maria Roberta Cilio, David A. Clark, Jane Cleary-Goldman, Ethel G. Clemente, John A. Clements, Ronald I. Clyman, Susan S. Cohen, John Colombo, Richard M. Cowett, Peter A. Crawford, James E. Crowe, Luise A. Cullen-McEwen, Wayne S. Cutfield, Mary E. D'Alton, Enrico Danzer, Christophe Delacourt, Sherin U. Devaskar, Thomas G. Diacovo, Nikolina Docheva, John P. Dormans, Kevin Dysart, Afif El-Khuffash, Peter James Ellis, Kerry McGarr Empey, Baris Ercal, Melinda Erdős, Robert P. Erickson, Mohamed A. Fahim, Arij Faksh, Hans-Georg Frank, Philippe S. Friedlich, Jed Friedman, Yuansheng Gao, Marianne Garland, Donna Geddes, Michael K. Georgieff, Jason Gien, Dino A. Giussani, Armond S. Goldman, Efrén González, Misty Good, Denis M. Grant, Lucy R. Green, Emmanouil Grigoriou, Adda Grimberg, Ian Gross, Ruth E. Grunau, Jean-Pierre Guignard, Alistair Jan Gunn, Nursen Gurtunca, Alice Hadchouel, Gabriel G. Haddad, Henrik Hagberg, Thomas Hale, K. Michael Hambidge, Cathy Hammerman, Thor Willy Ruud Hansen, Mark A. Hanson, Richard Harding, Mary Catherine Harris, Peter Hartmann, Foteini Hassiotou, Guttorm Haugen, Colin P. Hawkes, William W. Hay, Christina E. Hayward, Vivi M. Heine, Ann Hellström, Michael A. Helmrath, Karen D. Hendricks-Muñoz, Emilio Herrera, Michael J. Hiatt, Steven B. Hoath, Stuart B. Hooper, Stephen A. Huang, Silvia Iacobellli, Terrie E. Inder, M. Luisa Iruela-Arispe, Sudarshan R. Jadcherla, Deepak Jain, Thomas Jansson, John Lynn Jefferies, Jennifer G. Jetton, Alan H. Jobe, Lois H. Johnson, Richard B. Johnston, Rebecca Lee Jones, Pedro A. Jose, Satish C. Kalhan, Suhas G. Kallapur, Michael Kaplan, Stanley Kaplan, Heidi Eigenrauch Karpen, Saul J. Karpen, S. Ananth Karumanchi, Frederick J. Kaskel, Anup C. Katheria, Lorraine E. Levitt Katz, Susan E. Keeney, Steven E. Kern, Shirin Khanjani, Laurie E. Kilpatrick, Chang-Ryul Kim, John P. Kinsella, Torvid Kiserud, Joyce M. Koenig, Tobias R. Kollmann, Jay K. Kolls, Nancy F. Krebs, Thomas J. Kulik, Jessica Katz Kutikov, Satyan Lakshminrusimha, Angelo A. Lamola, Miguel Angel Lasunción, Pascal M. Lavoie, Tucker W. LeBien, Mary M. Lee, Matthew K. Lee, Yvonne K. Lee, Sandra Leibel, Fred Levine, Ofer Levy, Yang Liu, Steven Lobritto, Cynthia A. Loomis, Colleen A. Lopez, David A. MacIntyre, Maxime M. Mahe, Akhil Maheshwari, Anastasiya Mankouski, Carlos B. Mantilla, Arnaud Marchant, Kara Gross Margolis, M. Michele Mariscalco, László Maródi, Karel Maršál, Richard J. Martin, Douglas G. Matsell, Dwight E. Matthews, Harry J. McArdle, James L. McManaman, Patrick J. McNamara, Patrick S. McQuillen, Tim C. McQuinn, Judith S. Mercer, Giacomo Meschia, Steven P. Miller, Parviz Minoo, Paul Monagle, Jacopo P. Mortola, Louis J. Muglia, Upender K. Munshi, Ran Namgung, Sumana Narasimhan, Jan Nedergaard, Josef Neu, Sanjay K. Nigam, Lawrence M. Nogee, Shahab Noori, Barbara M. O'Brien, Robin K. Ohls, Henar Ortega-Senovilla, Justin M. O'Sullivan, Sarah A. Owusu, Abhijeet Pal, Howard B. Panitch, Anna A. Penn, Raymond B. Penn, Cameron Pernia, Anthony F. Philipps, Joseph A. Picoraro, Francesco Pisani, David Pleasure, Jeanette R. Pleasure, Samuel J. Pleasure, Scott L. Pomeroy, Martin Post, Y.S. Prakash, Joshua D. Prozialeck, Theodore J. Pysher, Raymond Quigley, Marlene Rabinovitch, Thomas M. Raffay, J. Usha Raj, Haley Ramsey, Sarosh Rana, Tara Marie Randis, Manon Ranger, Adam J. Ratner, Timothy R.H. Regnault, Henrique Rigatto, Natalie E. Rintoul, Roberto Romero, James C. Rose, Charles R. Rosenfeld, A. Catharine Ross, Henry J. Rozycki, Thomas D. Ryan, Rakesh Sahni, Eniko Sajti, Harvey B. Sarnat, Lisa M. Satlin, Ola Didrik Saugstad, William Schierding, Frank C. Schmalstieg, George J. Schwartz, Jeffrey Schwartz, Jeffrey L. Segar, David T. Selewski, Istvan Seri, Thomas H. Shaffer, Kara N. Shah, Martin J. Shearer, Sharareh Shojaie, Noah F. Shroyer, Colin P. Sibley, Gary C. Sieck, Rebecca A. Simmons, Emidio M. Sivieri, Francine G. Smith, Lois E.H. Smith, Ian M. Smyth, Brian S. Snarr, Evan Y. Snyder, Martha Sola-Visner, Michael J. Solhaug, Mark A. Sperling, Lakshmi Srinivasan, Andreas Stahl, Charles A. Stanley, Robin H. Steinhorn, Barbara S. Stonestreet, Janette F. Strasburger, Dennis M. Styne, Lori Sussel, Emily W.Y. Tam, Libo Tan, Claire Thornton, Daniel J. Tollin, Beáta Tóth, Jeffrey A. Towbin, Ashley Trocle, William E. Truog, Reginald C. Tsang, Kristin M. Uhler, John N. Van Den Anker, Johannes (Hans) B. van Goudoever, Susan J. Vannucci, Mark H. Vickers, Daniela Virgintino, Joseph J. Volpe, Neeta L. Vora, Neha V. Vyas, Annette Wacker-Gussmann, Megan J. Wallace, Brian H. Walsh, Alice M. Wang, David Warburton, Robert M. Ward, Kristi L. Watterberg, Lynne A. Werner, Barry K. Wershil, Susan E. Wert, Andy Wessels, Jeffrey A. Whitsett, Michael Wise, Matthias T. Wolf, Marla R. Wolfson, Hector R. Wong, James L. Wynn, Lami Yeo, Stephen Yip, Bradley A Yoder, Mervin C. Yoder, Momoko Yoshimoto, Christopher J. Yuskaitis, Dan Zhou, and Ann Zovein

Published
2017
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results