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

• Published in: Journal of the American Society of Nephrology Vol. 28; no. 3; pp. 761 - 768
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01-03-2017
• Subjects: Animals; Brief Communications; Crystallization; Humans; Hyperoxaluria - complications; Hyperoxaluria - metabolism; Kidney Calculi - etiology; Mice; Mice, Inbred C57BL; Receptors, Tumor Necrosis Factor, Type I - physiology; Receptors, Tumor Necrosis Factor, Type II - physiology; Hyperoxaluria; pathology; Chronic inflammation; Kidney stone
• DOI: 10.1681/asn.2016040486
• EISSN: 1533-3450
• ISSN: 1046-6673

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
, and
deficient mice did not. Despite identical levels of hyperoxaluria,
, and
-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
and
, 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.