title: Protein kinase C α inhibition prevents peritoneal damage in a mouse model of chronic peritoneal exposure to high-glucose dialysate.
abstract: Chronic exposure to commercial glucose-based peritoneal dialysis fluids during peritoneal dialysis induces peritoneal membrane damage leading to ultrafiltration failure. In this study the role of protein kinase C (PKC) α in peritoneal membrane damage was investigated in a mouse model of peritoneal dialysis. We used 2 different approaches: blockade of biological activity of PKCα by intraperitoneal application of the conventional PKC inhibitor Go6976 in C57BL/6 wild-type mice and PKCα-deficient mice on a 129/Sv genetic background. Daily administration of peritoneal dialysis fluid for 5 weeks induced peritoneal upregulation and activation of PKCα accompanied by epithelial-to-mesenchymal transition of peritoneal mesothelial cells, peritoneal membrane fibrosis, neoangiogenesis, and macrophage and T cell infiltration, paralleled by reduced ultrafiltration capacity. All pathological changes were prevented by PKCα blockade or deficiency. Moreover, treatment with Go6976 and PKCα deficiency resulted in strong reduction of proinflammatory, profibrotic, and proangiogenic mediators. In cell culture experiments, both treatment with Go6976 and PKCα deficiency prevented peritoneal dialysis fluid-induced release of MCP-1 from mouse peritoneal mesothelial cells and ameliorated transforming growth factor-β1-induced epithelial-to-mesenchymal transition and peritoneal dialysis fluid-induced MCP-1 release in human peritoneal mesothelial cells. Thus, PKCα plays a crucial role in the pathophysiology of peritoneal membrane dysfunction induced by peritoneal dialysis fluids, and we suggest that its therapeutic inhibition might be a valuable treatment option for peritoneal dialysis patients.
authors.affiliation: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany; Department of Nephrology, Tongji-Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Balzer
authors.affiliation: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.
authors.forename: Song
authors.initials: S
authors.lastname: Rong
authors.affiliation: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Menne
authors.affiliation: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: von Vietinghoff
authors.affiliation: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.
authors.forename: Lei
authors.initials: L
authors.lastname: Dong
authors.affiliation: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.
authors.forename: Faikah
authors.initials: F
authors.lastname: Gueler
authors.affiliation: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Jang
authors.affiliation: Department of Nephrology, Tongji-Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Clinic for General, Abdominal and Transplant Surgery, Medical School Hannover, Hannover, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Timrott
authors.affiliation: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.
authors.forename: Sergey
authors.initials: S
authors.lastname: Tkachuk
authors.affiliation: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Hiss
authors.affiliation: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.affiliation: Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany; Phenos GmbH, Hannover, Germany. Electronic address: nshushakova@phenos.com.
authors.forename: Nelli
authors.initials: N
authors.lastname: Shushakova
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000627:therapeutic use*; D002460:Cell Line; D015314:Dialysis Solutions / Q000009:adverse effects*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005434:Flow Cytometry; D005947:Glucose / Q000009:adverse effects*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D056627:Peritoneal Fibrosis / Q000517:prevention & control*; D010537:Peritoneum / Q000166:cytology / Q000473:pathology; D061251:Primary Cell Culture; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002227:Carbazoles; D015314:Dialysis Solutions; D004791:Enzyme Inhibitors; D053773:Transforming Growth Factor beta1; C081021:Go 6976; C496628:PRKCA protein, human; C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha; D005947:Glucose
keywords: cytokines; fibrosis; inflammation; peritoneal dialysis; peritoneal membrane; signaling