Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in 1 C 57 BL / 6 mice 2 3

Chronic kidney disease (CKD) research is limited by the lack of convenient inducible models mimicking human CKD and its complications in experimental animals. We demonstrate that a soluble oxalate-rich diet induces stable stages of CKD in male and female C57BL/6 mice. Renal histology is characterized by tubular damage, remnant atubular glomeruli, interstitial inflammation, and fibrosis with the extent of tissue involvement depending on the duration of oxalate feeding. Expression profiling of markers and magnetic resonance imaging findings established to reflect inflammation and fibrosis parallel the histological changes. Within 3 weeks the mice reproducibly develop normochromic anemia, metabolic acidosis, hyperkalemia, FGF23 activation, hyperphosphatemia and hyperparathyroidism. In addition, the model is characterized by profound arterial hypertension as well as cardiac fibrosis that persist following the switch to a control diet. Together, this new model of inducible CKD overcomes a number of previous experimental limitations and should serve useful in research related to CKD and its complications. DOI: https://doi.org/10.1152/ajprenal.00488.2015 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-124084 Accepted Version Originally published at: Mulay, Shrikant Ramesh; Eberhard, Jonathan Nicodemos; Pfann, Victoria; Marschner, Julian A; Darisipudi, Murthy Narayana; Daniel, Christoph; Romoli, Simone; Desai, Jyaysi; Grigorescu, Melissa; Kumar, Santosh V; Rathkolb, Birgit; Wolf, Eckhard; Hrabě de Angelis, Martin; Bäuerle, Tobias; Dietel, Barbara; Wagner, Carsten A; Amann, Kerstin; Eckardt, Kai-Uwe; Aronson, Peter S; Anders, Hans Joachim; Knauf, Felix (2016). Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in C57BL/6 mice. American Journal of Physiology. Renal, Fluid and Electrolyte Physiology, 310(8):785-795. DOI: https://doi.org/10.1152/ajprenal.00488.2015 1 Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in 1 C57BL/6 mice 2 3 Shrikant R. Mulay*, Jonathan N. Eberhard*, Victoria Pfann*, Julian A. Marschner, Murthy N. 4 Darisipudi, Christoph Daniel, Simone Romoli, Jyaysi Desai, Melissa Grigorescu, Santhosh V. 5 Kumar, Birgit Rathkolb, Eckhard Wolf, Martin Hrabě de Angelis, Tobias Bäuerle, Barbara 6 Dietel, Carsten A. Wagner, Kerstin Amann, Kai-Uwe Eckardt, Peter S. Aronson, Hans 7 Joachim Anders*, Felix Knauf* 8 *Indicates equal contribution 9 10 1 Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany 11 2 Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen12 Nürnberg (FAU), Erlangen, Germany 13 3 Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 14 Erlangen, Germany 15 4 German Mouse Clinic, Institute of Experimental Genetics, Helmholtz-Zentrum München, 16 Neuherberg, Germany 17 5 Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians18 University München, Munich, Germany 19 6 Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität 20 München, Freising, Germany 21 7 German Center for Diabetes Research (DZD), Neuherberg, Germany 22 8 Preclinical Imaging Platform Erlangen, Institute of Radiology, Friedrich-Alexander-Universität 23 Erlangen-Nürnberg (FAU), Erlangen, Germany 24 9 Department of Cardiology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 25 Erlangen, Germany 26 10 Zurich Center for Integrative Human Physiology, Zurich, Switzerland 27 11 Department of Internal Medicine, Yale University School of Medicine, New Haven, 28 Connecticut, USA 29 30 Number of text pages: 15, Number of figures: 7, Number of tables: 2, 31 Number of supplementary tables: 1, 32 Word count of abstract: 154; of manuscript: 3070 33 Short title: Oxalate-induced CKD mouse model 34 Corresponding author: 35 Felix Knauf, M.D. 36 Department of Nephrology and Hypertension 37 Friedrich-Alexander-Universität (FAU) 38 Universitätsklinikum Erlangen 39 Schwabachanlage 12 40 91054 Erlangen, Germany 41 Tel.: +49-9131-85-39572 42 Fax: +49-9131-85-39561 43 Email: Felix.Knauf@uk-erlangen.de 44 45 Articles in PresS. Am J Physiol Renal Physiol (January 13, 2016). doi:10.1152/ajprenal.00488.2015 Copyright © 2016 by the American Physiological Society. 2 Abstract 46 Chronic kidney disease (CKD) research is limited by the lack of convenient inducible 47 models mimicking human CKD and its complications in experimental animals. We demonstrate 48 that a soluble oxalate-rich diet induces stable stages of CKD in male and female C57BL/6 mice. 49 Renal histology is characterized by tubular damage, remnant atubular glomeruli, interstitial 50 inflammation, and fibrosis with the extent of tissue involvement depending on the duration of 51 oxalate feeding. Expression profiling of markers and magnetic resonance imaging findings 52 established to reflect inflammation and fibrosis parallel the histological changes. Within 3 weeks 53 the mice reproducibly develop normochromic anemia, metabolic acidosis, hyperkalemia, FGF23 54 activation, hyperphosphatemia and hyperparathyroidism. In addition, the model is 55 characterized by profound arterial hypertension as well as cardiac fibrosis that persist following 56 the switch to a control diet. Together, this new model of inducible CKD overcomes a number of 57 previous experimental limitations and should serve useful in research related to CKD and its 58 complications. 59 60