Hyperoxaluria requires TNF Receptors to initiate crystal adhesion and kidney stone disease

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

Research output: Contribution to journalArticle

25 Scopus citations

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 hyperoxaluriarelated CKD. Immunohistochemical analysis revealed upregulated tubular expression of TNFR1 and TNFR2 in human andmurine kidneys with calciumoxalate (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-Typemice. 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 treatmentwith the smallmolecule 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.

Original languageEnglish (US)
Pages (from-to)761-768
Number of pages8
JournalJournal of the American Society of Nephrology
Volume28
Issue number3
DOIs
StatePublished - Mar 2017

ASJC Scopus subject areas

  • Nephrology

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    Mulay, S. R., Eberhard, J. N., Desai, J., Marschner, J. A., Kumar, S. V. R., Weidenbusch, M., Grigorescu, M., Lech, M., Eltrich, N., Müller, L., Hans, W., De Angelis, M. H., Vielhauer, V., Hoppe, B., Asplin, J., Burzlaff, N., Herrmann, M., Evan, A., & Anders, H. J. (2017). Hyperoxaluria requires TNF Receptors to initiate crystal adhesion and kidney stone disease. Journal of the American Society of Nephrology, 28(3), 761-768. https://doi.org/10.1681/ASN.2016040486