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Cyclooxygenase-2 Mediates Dialysate-Induced Alterations of the Peritoneal Membrane

Luiz S. Aroeira^*,, Enrique Lara-Pezzi^*,, Jesús Loureiro^*,, Abelardo Aguilera^*,, Marta Ramírez-Huesca^*,, Guadalupe González-Mateo^*,, M. Luisa Pérez-Lozano^*,, Patricia Albar-Vizcaíno^*,, M-Auxiliadora Bajo^*,, Gloria del Peso^*,, José Antonio Sánchez-Tomero^*,, José Antonio Jiménez-Heffernan^*,||, Rafael Selgas^*, and Manuel López-Cabrera^*,,¶

^* Instituto Reina Sofía de Investigaciones Nefrológicas, Unidad de Investigación and Servicio de Nefrología, Hospital Universitario La Paz, Unidad de Biología Molecular and Servicio de Nefrología, Hospital Universitario de la Princesa, ^|| Servicio de Anatomía Patológica, Hospital Universitario Puerta de Hierro, and ^¶ Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain

Correspondence: Dr. Manuel López-Cabrera, Unidad de Biología Molecular, Hospital Universitario de la Princesa, C/ Diego de León No. 62, 28006-Madrid, Spain. Phone: 34-91-5202334; Fax: 34-91-5202374; E-mail: mlopez.hlpr{at}salud.madrid.org

Received for publication February 22, 2008. Accepted for publication October 27, 2008.

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.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673