Cyclooxygenase-2 mediates dialysate-induced alterations of the peritoneal membrane.
During peritoneal dialysis (PD), exposure of the peritoneal membrane to nonphysiologic solutions causes inflammation, ultimately leading to altered structure and function. Myofibroblasts, one of the cell types that contribute to dysfunction of the peritoneal membrane, can originate from mesothelial cells (MCs) by epithelial-to-mesenchymal transition (EMT), a process that has been associated with an increased rate of peritoneal transport. Because cyclooxygenase-2 (COX-2) is induced by inflammation, we studied the role of COX-2 in the deterioration of the peritoneal membrane. We observed that nonepithelioid MCs found in peritoneal effluent expressed higher levels of COX-2 than epithelioid MCs. The mass transfer coefficient for creatinine correlated with MC phenotype and with COX-2 levels. Although COX-2 was upregulated during EMT of MCs in vitro, COX-2 inhibition did not prevent EMT. In a mouse model of PD, however, COX-2 inhibition with Celecoxib resulted in reduced fibrosis and in partial recovery of ultrafiltration, outcomes that were associated with a reduction of inflammatory cells. Furthermore, PD fluid with a low content of glucose degradation products did not induce EMT or COX-2; the peritoneal membranes of mice treated with this fluid showed less worsening than mice exposed to standard fluid. In conclusion, upregulation of COX-2 during EMT may mediate peritoneal inflammation, suggesting COX-2 inhibition as a potential strategy to ameliorate peritoneal deterioration in PD patients.
Aroeira
Luiz S
LS
Instituto Reina Sofía de Investigaciones Nefrológicas, Hospital Universitario La Paz, Madrid, Spain.
Lara-Pezzi
Enrique
E
Loureiro
Jesús
J
Aguilera
Abelardo
A
Ramírez-Huesca
Marta
M
González-Mateo
Guadalupe
G
Pérez-Lozano
M Luisa
ML
Albar-Vizcaíno
Patricia
P
Bajo
M-Auxiliadora
MA
del Peso
Gloria
G
Sánchez-Tomero
José Antonio
JA
Jiménez-Heffernan
José Antonio
JA
Selgas
Rafael
R
López-Cabrera
Manuel
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001693:Biological Transport, Active; D000068579:Celecoxib; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015314:Dialysis Solutions / Q000009:adverse effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D023421:Models, Animal; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D010537:Peritoneum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation; D055815:Young Adult
D052246:Cyclooxygenase 2 Inhibitors; D015314:Dialysis Solutions; D011720:Pyrazoles; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D013449:Sulfonamides; D014157:Transcription Factors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib