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Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease
- Source :
- J. Am. Soc. Nephrol. 28, 761-768 (2016)
- Publication Year :
- 2016
-
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.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Urology
Necroptosis
030232 urology & nephrology
Calcium oxalate
Inflammation
urologic and male genital diseases
Receptors, Tumor Necrosis Factor
Primary hyperoxaluria
03 medical and health sciences
chemistry.chemical_compound
Kidney Calculi
Mice
0302 clinical medicine
Internal medicine
medicine
Chronic Inflammation
Hyperoxaluria
Kidney Stone
Pathology
Animals
Humans
Receptors, Tumor Necrosis Factor, Type II
Receptor
business.industry
Cell adhesion molecule
Adhesion
General Medicine
medicine.disease
Mice, Inbred C57BL
030104 developmental biology
Endocrinology
chemistry
Kidney stone disease
Nephrology
Receptors, Tumor Necrosis Factor, Type I
Tumor necrosis factor alpha
Nephrocalcinosis
medicine.symptom
Brief Communications
business
Crystallization
Annexin A2
Subjects
Details
- ISSN :
- 15333450
- Volume :
- 28
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of the American Society of Nephrology : JASN
- Accession number :
- edsair.doi.dedup.....53ef7210ad0876fd2c202dd7bfa182b9