Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease.
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, whereasTnfr1-, Tnfr2-, andTnfr1/2-deficient mice did not. Despite identical levels of hyperoxaluria,Tnfr1-, Tnfr2-, andTnfr1/2-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 cellsin vitroandin 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.
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Shrikant R
SR
Mulay
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Jonathan N
JN
Eberhard
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Jyaysi
J
Desai
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Julian A
JA
Marschner
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Santhosh V R
SV
Kumar
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Marc
M
Weidenbusch
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Melissa
M
Grigorescu
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Maciej
M
Lech
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Nuru
N
Eltrich
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.
Lisa
L
Müller
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz-Zentrum München, Neuherberg, Germany.
Wolfgang
W
Hans
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.
Martin
M
Hrabě de Angelis
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
Volker
V
Vielhauer
Department of Pediatrics, University Medical Center, Bonn, Germany.
Bernd
B
Hoppe
Litholink Corporation, Laboratory Corporation of America Holdings, Chicago, Illinois.
John
J
Asplin
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.
Nicolai
N
Burzlaff
Department for Internal Medicine 3, University Hospital Erlangen, Institute for Clinical Immunology, Erlangen, Germany; and.
Martin
M
Herrmann
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana.
Andrew
A
Evan
Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany; hjanders@med.uni-muenchen.de.
Hans-Joachim
HJ
Anders
D000818:Animals; D003460:Crystallization; D006801:Humans; D006959:Hyperoxaluria / Q000150:complications* / Q000378:metabolism; D007669:Kidney Calculi / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000502:physiology*
D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II
Chronic inflammation; Hyperoxaluria; Kidney stone; pathology