Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease

Mulay SR, Eberhard JN, Desai J, Marschner JA, Kumar SV, Weidenbusch M, Grigorescu M, Lech M, Eltrich N, Müller L, Hans W, Hrabě de Angelis M, Vielhauer V, Hoppe B, Asplin J, Burzlaff N, Herrmann M, Evan A, Anders HJ (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Journal of the American Society of Nephrology American Society of Nephrology

DOI: 10.1681/ASN.2016040486

Abstract

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.

Authors with CRIS profile

Lisa Müller Professur für Anorganische Chemie Nicolai Burzlaff Professur für Anorganische Chemie Martin Herrmann Department of Medicine 3 – Rheumatology and Immunology

Involved external institutions

Klinikum der Universität München (Großhadern und Innenstadt) DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Laboratory Corporation of America US United States (USA) (US) Indiana University – Purdue University Indianapolis US United States (USA) (US) Universitätsklinikum Bonn DE Germany (DE)

How to cite

APA:

Mulay, S.R., Eberhard, J.N., Desai, J., Marschner, J.A., Kumar, S.V., Weidenbusch, M.,... Anders, H.J. (2016). Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease. Journal of the American Society of Nephrology. https://dx.doi.org/10.1681/ASN.2016040486

MLA:

Mulay, Shrikant R., et al. "Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease." Journal of the American Society of Nephrology (2016).

BibTeX: Download