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

摘要: Intrarenal crystals trigger inflammation and renal cell necroptosis, processes that involve TNF receptor (TNFR) signaling. Here, we tested the hypothesis TNFRs also have a direct role in tubular crystal deposition progression of hyperoxaluria-related CKD. Immunohistochemical analysis revealed upregulated expression TNFR1 TNFR2 human murine kidneys with calcium oxalate (CaOx) nephrocalcinosis-related CKD compared controls. Western blot mRNA analyses mice yielded consistent data. When fed an oxalate-rich diet, wild-type developed progressive CKD, whereas Tnfr1-, Tnfr2-, Tnfr1/2-deficient did not. Despite identical levels hyperoxaluria, lacked intrarenal CaOx damage observed mice. Inhibition TNFR signaling prevented induced adhesion molecules, CD44 annexin II, epithelial cells vitro vivo, treatment small molecule inhibitor R-7050 partially protected hyperoxaluric from nephrocalcinosis We conclude is essential for to luminal membrane tubules as fundamental initiating mechanism nephropathy. Furthermore, therapeutic blockade might delay forms nephropathy, such primary hyperoxaluria.