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

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)761-768
Number of pages8
JournalJournal of the American Society of Nephrology : JASN
Volume28
Issue number3
DOIs
StatePublished - Mar 1 2017

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Hyperoxaluria
Kidney Calculi
Tumor Necrosis Factor Receptors
Kidney Diseases
Nephrocalcinosis
Calcium Oxalate
Oxalates
Kidney
Primary Hyperoxaluria
Annexin A2
Receptors, Tumor Necrosis Factor, Type II
Receptors, Tumor Necrosis Factor, Type I
Western Blotting
Epithelial Cells
Diet
Inflammation
Messenger RNA
Membranes

Keywords

  • Chronic inflammation
  • Hyperoxaluria
  • Kidney stone
  • pathology

ASJC Scopus subject areas

  • Nephrology

Cite this

Mulay, S. R., Eberhard, J. N., Desai, J., Marschner, J. A., Kumar, S. V. R., Weidenbusch, M., ... Anders, H. J. (2017). Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease. Journal of the American Society of Nephrology : JASN, 28(3), 761-768. https://doi.org/10.1681/ASN.2016040486

Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease. / Mulay, Shrikant R.; Eberhard, Jonathan N.; Desai, Jyaysi; Marschner, Julian A.; Kumar, Santhosh V.R.; Weidenbusch, Marc; Grigorescu, Melissa; Lech, Maciej; Eltrich, Nuru; Müller, Lisa; Hans, Wolfgang; Hrabě de Angelis, Martin; Vielhauer, Volker; Hoppe, Bernd; Asplin, John; Burzlaff, Nicolai; Herrmann, Martin; Evan, Andrew; Anders, Hans Joachim.

In: Journal of the American Society of Nephrology : JASN, Vol. 28, No. 3, 01.03.2017, p. 761-768.

Research output: Contribution to journalArticle

Mulay, SR, Eberhard, JN, Desai, J, Marschner, JA, Kumar, SVR, 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 2017, 'Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease', Journal of the American Society of Nephrology : JASN, vol. 28, no. 3, pp. 761-768. https://doi.org/10.1681/ASN.2016040486
Mulay, Shrikant R. ; Eberhard, Jonathan N. ; Desai, Jyaysi ; Marschner, Julian A. ; Kumar, Santhosh V.R. ; Weidenbusch, Marc ; Grigorescu, Melissa ; Lech, Maciej ; Eltrich, Nuru ; Müller, Lisa ; Hans, Wolfgang ; Hrabě de Angelis, Martin ; Vielhauer, Volker ; Hoppe, Bernd ; Asplin, John ; Burzlaff, Nicolai ; Herrmann, Martin ; Evan, Andrew ; Anders, Hans Joachim. / Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease. In: Journal of the American Society of Nephrology : JASN. 2017 ; Vol. 28, No. 3. pp. 761-768.
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