Journal
FASEB JOURNAL
Volume 33, Issue 11, Pages 12036-12046Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201900016RR
Keywords
Bruton's tyrosine kinase; CaP; CKD
Categories
Funding
- Landseed Hospital-NCU joint grants [106/107]
- National Health Research Institutes (NHRI) [NHRIEX106-10607SI]
- Ministry of Science and Technology (MOST) [107-2314-B-008 -001, 107-2622-B-008-002-CC1, 106/107-2622-B-008-001-CC1]
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Uremic pruritus with elevated levels of calcium phosphate (CaP) in skin is a common symptom in patients with chronic kidney disease (CKD). In this study, we demonstrate that intradermal injection of CaP into mice triggered scratching by up-regulating the IL-6 in skin and phosphorylation of ERKs in dorsal root ganglion (DRG) in a dose-dependent manner. IL-6 is essential because the CaP-induced up-regulation of phosphorylated (p)-ERK in DRG was considerably reduced in the IL-6 knockout mice. Microarray analysis in conjunction with real-time PCR revealed a higher mRNA expression of Bruton's tyrosine kinase (BTK) gene in DRG after CaP injection. The inhibition of BTK by ibrutinib noticeably diminish the CaP-induced up-regulation of IL-6 and p-ERK in mice. A high amount of IL-6 was detected in itchy skin and blood of patients with CKD. The expressions of p-BTK and p-ERK in DRG primary cells reached maximum levels at 1 and 10 min, respectively, after treatment of recombinant IL-6 and were significantly reduced by treatment of IL-6 along with ibrutinib. The mechanism by which the CaP-induced pruritus mediated by the IL-6/p-BTK/p-ERK signaling was revealed.
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