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Molecular Medicine

, Volume 14, Issue 11–12, pp 724–730 | Cite as

Inhibition of COX 1 and 2 prior to Renal Ischemia/Reperfusion Injury Decreases the Development of Fibrosis

  • Carla Q. Feitoza
  • Giselle M. Gonçalves
  • Patricia Semedo
  • Marcos A. Cenedeze
  • Hélady S. Pinheiro
  • Felipe Caetano Beraldo
  • Oscar Fernando
  • Pavão dos Santos
  • Vicente de Paula A. Teixeira
  • Marlene A. dos Reis
  • Marilda Mazzali
  • Alvaro Pacheco-Silva
  • Niels Olsen Saraiva Câmara
Research Article

Abstract

Ischemia and reperfusion injury (IRI) contributes to the development of chronic interstitial fibrosis/tubular atrophy in renal allograft patients. Cyclooxygenase (COX) 1 and 2 actively participate in acute ischemic injury by activating endothelial cells and inducing oxidative stress. Furthermore, blockade of COX 1 and 2 has been associated with organ improvement after ischemic damage. The aim of this study was to evaluate the role of COX 1 and 2 in the development of fibrosis by performing a COX 1 and 2 blockade immediately before IRI. We subjected C57Bl/6 male mice to 60 min of unilateral renal pedicle occlusion. Prior to surgery mice were either treated with indomethacin (IMT) at days −1 and 0 or were untreated. Blood and kidney samples were collected 6 wks after IRI. Kidney samples were analyzed by real-time reverse transcription-polymerase chain reaction for expression of transforming growth factor β (TGF-β), monocyte chemoattractant protein 1 (MCP-1), osteopontin (OPN), tumor necrosis factor a (TNF-α), interleukin (IL)-1β, IL-10, heme oxygenase 1 (HO-1), vimentin, connective-tissue growth factor (CTGF), collagen I, and bone morphogenic protein 7 (BMP-7). To assess tissue fibrosis we performed morphometric analyses and Sirius red staining. We also performed immunohistochemical analysis of anti-actin smooth muscle. Renal function did not significantly differ between groups. Animals pretreated with IMT showed significantly less interstitial fibrosis than nontreated animals. Gene transcript analyses showed decreased expression of TGF-β, MCP-1, TNF-α, IL-1-β, vimentin, collagen I, CTGF, and IL-10 mRNA (all P < 0.05). Moreover, HO-1 mRNA was increased in animals pretreated with IMT (P < 0.05). Conversely, IMT treatment decreased osteopontin expression and enhanced BMP-7 expression, although these levels did not reach statistical significance when compared with control expression levels. The blockade of COX 1 and 2 resulted in less tissue fibrosis, which was associated with a decrease in proinflammatory cytokines and enhancement of the protective cellular response.

Notes

Acknowledgments

This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico and Fundação de Amparo à Pesquisa of São Paulo (Grant numbers: 04/08311-4, 04/13449-7, 06/03982-5, and 07/07139-3).

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Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Carla Q. Feitoza
    • 1
    • 4
  • Giselle M. Gonçalves
    • 1
    • 4
  • Patricia Semedo
    • 1
    • 4
  • Marcos A. Cenedeze
    • 1
    • 4
  • Hélady S. Pinheiro
    • 2
    • 4
  • Felipe Caetano Beraldo
    • 3
    • 4
  • Oscar Fernando
    • 4
  • Pavão dos Santos
    • 1
    • 4
  • Vicente de Paula A. Teixeira
    • 3
    • 4
  • Marlene A. dos Reis
    • 3
    • 4
  • Marilda Mazzali
    • 3
    • 4
  • Alvaro Pacheco-Silva
    • 1
    • 4
  • Niels Olsen Saraiva Câmara
    • 1
    • 4
    • 5
  1. 1.Laboratory of Experimental and Clinical Immunology, Nephrology DivisionFederal University of São PauloSão PauloBrazil
  2. 2.Nephrology DivisionFederal University of Juiz de ForaMinas GeraisBrazil
  3. 3.PathologyFederal University of Triângulo MineiroUberaba, Minas GeraisBrazil
  4. 4.Nephrology DivisionState University of CampinasCampinas, São PauloBrazil
  5. 5.Transplantation Immunobiology Laboratory, Department of Immunology, Institute of Biomedical Sciences IVUniversity of São PauloSão PauloBrazil

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