Intrarenal crystals trigger inflammation and renal cell necroptosis, processes that involve TNF receptor (TNFR) signaling. Here, we tested the hypothesis that TNFRs also have a direct role in tubular crystal deposition and progression of hyperoxaluria-related CKD. Immunohistochemical analysis revealed upregulated tubular expression of TNFR1 and TNFR2 in human and murine kidneys with calcium oxalate (CaOx) nephrocalcinosis-related CKD compared with controls. Western blot and mRNA expression analyses in mice yielded consistent data. When fed an oxalate-rich diet, wild-type mice developed progressive CKD, whereas Tnfr1-, Tnfr2-, and Tnfr1/2-deficient mice did not. Despite identical levels of hyperoxaluria, Tnfr1-, Tnfr2-, and Tnfr1/2-deficient mice also lacked the intrarenal CaOx deposition and tubular damage observed in wild-type mice. Inhibition of TNFR signaling prevented the induced expression of the crystal adhesion molecules, CD44 and annexin II, in tubular epithelial cells in vitro and in vivo, and treatment with the small molecule TNFR inhibitor R-7050 partially protected hyperoxaluric mice from nephrocalcinosis and CKD. We conclude that TNFR signaling is essential for CaOx crystal adhesion to the luminal membrane of renal tubules as a fundamental initiating mechanism of oxalate nephropathy. Furthermore, therapeutic blockade of TNFR might delay progressive forms of nephrocalcinosis in oxalate nephropathy, such as primary hyperoxaluria.
Journal of the American Society of Nephrology : JASN. 2016 Sep 09 [Epub ahead of print]
Shrikant R Mulay, Jonathan N Eberhard, Jyaysi Desai, Julian A Marschner, Santhosh V R Kumar, Marc Weidenbusch, Melissa Grigorescu, Maciej Lech, Nuru Eltrich, Lisa Müller, Wolfgang Hans, Martin Hrabě de Angelis, Volker Vielhauer, Bernd Hoppe, John Asplin, Nicolai Burzlaff, Martin Herrmann, Andrew Evan, Hans-Joachim Anders
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany;, Department of Chemistry and Pharmacy and Interdisciplinary Center for Molecular Materials, Inorganic Chemistry and Interdisciplinary Center for Molecular Materials, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany;, German Mouse Clinic, Institute of Experimental Genetics, Helmholtz-Zentrum München, Neuherberg, Germany;, German Mouse Clinic, Institute of Experimental Genetics, Helmholtz-Zentrum München, Neuherberg, Germany; Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians University München, Munich, Germany; German Center for Diabetes Research, Neuherberg, Germany;, Department of Pediatrics, University Medical Center, Bonn, Germany;, Litholink Corporation, Laboratory Corporation of America Holdings, Chicago, Illinois;, Department for Internal Medicine 3, University Hospital Erlangen, Institute for Clinical Immunology, Erlangen, Germany; and., Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana., Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany; .