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 beta (TGF-beta), monocyte chemoattractant protein 1 (MCP-1), osteopontin (OPN), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1 beta, 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-beta, MCP-1, TNF-alpha, IL-1-beta, 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.
Highlights
In renal ischemia and reperfusion injury (IRI), inflammation results in changes in the endothelial cell phenotype
We observed an increase of mRNA for transforming growth factor β (TGF-β), OPN, vimentin, collagen I, and connective-tissue growth factor (CTGF) in ischemic kidneys compared with contralateral kidneys
IRI is the foremost antigen-independent factor related to the development of chronic allograft nephropathy, the leading cause of graft loss after the first year of renal transplantation
Summary
In renal ischemia and reperfusion injury (IRI), inflammation results in changes in the endothelial cell phenotype. These changes enhance leukocyte adhesion, entrapment, and transmigration, compromising the regional blood flow [1]. In the initial period of reperfusion, there is a rapid increase in proinflammatory cytokines, such as a tumor necrosis factor α (TNF-α) and interleukin (IL)-1β, induced in part by infiltrating mononuclear and endothelial cells [4,5]. COX 1 and 2 can be detected in kidney tissue subjected to IRI, and recent data from our group and other investigators have shown that first these molecules were upregulated after IRI, and that their activation has a negative impact on organ function outcome [7,8]. COX blockade was associated with an improvement in renal function and a decrease in reactive oxygen species [9,10]
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