Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease
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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: J AM SOC NEPHROL, Jahrgang 28, Nr. 3, 03.2017, S. 761-768.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease
AU - Mulay, Shrikant R
AU - Eberhard, Jonathan N
AU - Desai, Jyaysi
AU - Marschner, Julian A
AU - Kumar, Santhosh V R
AU - Weidenbusch, Marc
AU - Grigorescu, Melissa
AU - Lech, Maciej
AU - Eltrich, Nuru
AU - Müller, Lisa
AU - Hans, Wolfgang
AU - Hrabě de Angelis, Martin
AU - Vielhauer, Volker
AU - Hoppe, Bernd
AU - Asplin, John
AU - Burzlaff, Nicolai
AU - Herrmann, Martin
AU - Evan, Andrew
AU - Anders, Hans-Joachim
N1 - Copyright © 2017 by the American Society of Nephrology.
PY - 2017/3
Y1 - 2017/3
N2 - 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.
AB - 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.
KW - Animals
KW - Crystallization
KW - Humans
KW - Hyperoxaluria
KW - Kidney Calculi
KW - Mice
KW - Mice, Inbred C57BL
KW - Receptors, Tumor Necrosis Factor, Type I
KW - Receptors, Tumor Necrosis Factor, Type II
KW - Journal Article
U2 - 10.1681/ASN.2016040486
DO - 10.1681/ASN.2016040486
M3 - SCORING: Journal article
C2 - 27612997
VL - 28
SP - 761
EP - 768
JO - J AM SOC NEPHROL
JF - J AM SOC NEPHROL
SN - 1046-6673
IS - 3
ER -