title: 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.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Tiane
authors.initials: T
authors.lastname: Dai
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Nayak
authors.affiliation: Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Nast
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Quang
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Janine
authors.initials: J
authors.lastname: LaPage
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Andalibi
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Sharon G
authors.initials: SG
authors.lastname: Adler
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D015314:Dialysis Solutions / Q000009:adverse effects*; D004847:Epithelial Cells; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D009389:Neovascularization, Pathologic / Q000139:chemically induced; D009570:Nitriles; D010530:Peritoneal Dialysis / Q000009:adverse effects; D056627:Peritoneal Fibrosis / Q000139:chemically induced; D010537:Peritoneum / Q000098:blood supply / Q000473:pathology*; D010538:Peritonitis / Q000139:chemically induced / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines; D051381:Rats; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: C111835:CCL2 protein, human; C491766:Ccl2 protein, rat; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D015314:Dialysis Solutions; D009570:Nitriles; C512835:POSTN protein, human; C512836:Postn protein, rat; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C540383:ruxolitinib; D053612:Janus Kinases; D053148:Caspase 3