Janus kinase signaling activation mediates peritoneal inflammation and injury in vitro and in vivo in response to dialysate.

Abstract	Peritoneal membrane pathology limits long-term peritoneal dialysis (PD). Here, we tested whether JAK/STAT signaling is implicated and if its attenuation might be salutary. In cultured mesothelial cells, PD fluid activated, and the pan-JAK inhibitor P6 reduced, phospho-STAT1 and phospho-STAT3, periostin secretion, and cleaved caspase-3. Ex vivo, JAK was phosphorylated in PD effluent cells from long-term but not new PD patients. MCP-1 and periostin were increased in PD effluent in long term compared with new patients. In rats, twice daily, PD fluid infusion induced phospho-JAK, mesothelial cell hyperplasia, inflammation, fibrosis, and hypervascularity after 10 days of exposure to PD fluid. Concomitant instillation of a JAK1/2 inhibitor virtually completely attenuated these changes. Thus, our studies directly implicate JAK/STAT signaling in the mediation of peritoneal membrane pathology as a consequence of PD.
Authors	Tiane Dai, Ying Wang, Aditi Nayak, Cynthia C Nast, Lan Quang, Janine LaPage, Ali Andalibi, Sharon G Adler
Journal	Kidney international (Kidney Int) Vol. 86 Issue 6 Pg. 1187-96 (Dec 2014) ISSN: 1523-1755 [Electronic] United States
PMID	25007168 (Publication Type: Journal Article)
Chemical References	CCL2 protein, human Ccl2 protein, rat Cell Adhesion Molecules Chemokine CCL2 Dialysis Solutions Nitriles POSTN protein, human Postn protein, rat Protein Kinase Inhibitors Pyrazoles Pyrimidines STAT1 Transcription Factor STAT3 Transcription Factor ruxolitinib Janus Kinases Caspase 3
Topics	Animals Caspase 3 (metabolism) Cell Adhesion Molecules (metabolism) Cells, Cultured Chemokine CCL2 (metabolism) Dialysis Solutions (adverse effects) Epithelial Cells Female Humans Hyperplasia (chemically induced) Janus Kinases (antagonists & inhibitors, metabolism) Male Neovascularization, Pathologic (chemically induced) Nitriles Peritoneal Dialysis (adverse effects) Peritoneal Fibrosis (chemically induced) Peritoneum (blood supply, pathology) Peritonitis (chemically induced, metabolism) Phosphorylation Protein Kinase Inhibitors (pharmacology) Pyrazoles (pharmacology) Pyrimidines Rats STAT1 Transcription Factor (metabolism) STAT3 Transcription Factor (metabolism) Signal Transduction (drug effects) Time Factors

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