Abstract

Aims: Cytoglobin (CYGB) is a member of the mammalian globin family of respiratory proteins. Despite extensive research efforts, its physiological role remains largely unknown, but potential functions include reactive oxygen species (ROS) detoxification and signaling. Accumulating evidence suggests that ROS play a crucial role in podocyte detachment and apoptosis during diabetic kidney disease. This study aimed to explore the potential antioxidative renal role of CYGB both in vivo and in vitro.
Results: Using a Cygb-deficient mouse model, we demonstrate a Cygb-dependent reduction in renal function, coinciding with a reduced number of podocytes. To specifically assess the putative antioxidative function of CYGB in podocytes, we first confirmed high endogenous CYGB expression levels in two human podocyte cell lines and subsequently generated short hairpin RNA-mediated stable CYGB knockdown podocyte models. CYGB-deficient podocytes displayed increased cell death and accumulation of ROS as assessed by 2′7′-dichlorodihydrofluorescein diacetate assays and the redox-sensitive probe roGFP2-Orp1. CYGB-deficient cells also exhibited an impaired cellular bioenergetic status. Consistently, analysis of the CYGB-dependent transcriptome identified dysregulation of multiple genes involved in redox balance, apoptosis, as well as in chronic kidney disease (CKD). Finally, genome-wide association studies and expression studies in nephropathy biopsies indicate an association of CYGB with CKD.
Innovation: This study demonstrates a podocyte-related renal role of Cygb, confirms abundant CYGB expression in human podocyte cell lines, and describes for the first time an association between CYGB and CKD.
Conclusion: Our results provide evidence for an antioxidative role of CYGB in podocytes.

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cover image Antioxidants & Redox Signaling
Antioxidants & Redox Signaling
Volume 32Issue Number 16June 1, 2020
Pages: 1155 - 1171
PubMed: 31910047

History

Published in print: June 1, 2020
Published online: 28 April 2020
Published ahead of print: 6 February 2020
Published ahead of production: 7 January 2020
Accepted: 18 December 2019
Revision received: 28 November 2019
Received: 6 September 2019

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    Elisa B. Randi
    Department of Medicine/Physiology, University of Fribourg, Fribourg, Switzerland.
    Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
    National Centre of Competence in Research (NCCR) “Kidney.CH”, Zurich, Switzerland.
    Benjamin Vervaet
    Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
    Maria Tsachaki
    National Centre of Competence in Research (NCCR) “Kidney.CH”, Zurich, Switzerland.
    Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
    Elena Porto
    Institute of Organismal and Molecular Evolutionary Biology, University of Mainz, Mainz, Germany.
    Stijn Vermeylen
    Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
    Maja T. Lindenmeyer
    Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
    National Centre of Competence in Research (NCCR) “Kidney.CH”, Zurich, Switzerland.
    Nephrological Center, Medical Clinic and Policlinic IV, University of Munich, Munich, Germany.
    Le Thi Thanh Thuy
    Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
    Clemens D. Cohen
    Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
    National Centre of Competence in Research (NCCR) “Kidney.CH”, Zurich, Switzerland.
    Nephrological Center, Medical Clinic and Policlinic IV, University of Munich, Munich, Germany.
    Olivier Devuyst
    Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
    National Centre of Competence in Research (NCCR) “Kidney.CH”, Zurich, Switzerland.
    Andreas D. Kistler
    Division of Nephrology, Kantonsspital Frauenfeld, Frauenfeld, Switzerland.
    Csaba Szabo
    Chair of Pharmacology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
    Norifumi Kawada
    Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
    Thomas Hankeln
    Institute of Organismal and Molecular Evolutionary Biology, University of Mainz, Mainz, Germany.
    Alex Odermatt
    National Centre of Competence in Research (NCCR) “Kidney.CH”, Zurich, Switzerland.
    Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
    Sylvia Dewilde
    Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
    Roland H. Wenger
    Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
    National Centre of Competence in Research (NCCR) “Kidney.CH”, Zurich, Switzerland.
    David Hoogewijs [email protected]
    Department of Medicine/Physiology, University of Fribourg, Fribourg, Switzerland.
    National Centre of Competence in Research (NCCR) “Kidney.CH”, Zurich, Switzerland.

    Notes

    Address correspondence to: Prof. David Hoogewijs, Department of Medicine/Physiology, University of Fribourg, Fribourg 1700, Switzerland [email protected]

    Author Disclosure Statement

    No competing financial interests exist.

    Funding Information

    This work was supported by the Swiss National Science Foundation (grant 173000) and the German Research Foundation (grant HO5837/1-1) to D.H., a University Research Priority Program “Integrative Human Physiology” grant to E.B.R., the Biobank ERCB-KFB (Else Kröner-Fresenius-Foundation) to C.D.C., an intramural grant (Center for Computer Sciences, JGU Mainz) to T.H., the International PhD Program (IMB Mainz) to E.P. and T.H., a Grant-in-Aid for Scientific Research from JSPS (No. 25293177 and No. 16H05290) and a Grant for Research Program on Hepatitis from the Japan Agency for Medical Research and Development (18fk0210004h0003) to N.K., and the NCCR Kidney.CH financed by the SNF to C.D.C., O.D., A.O., R.H.W., and D.H.

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