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      Selective Cyclooxygenase-2 Inhibition Upregulates Renal Cortical α v Integrin Expression

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          Abstract

          Background: Cyclooxygenase-2 (COX-2), the inducible isoform of the cyclooxygenases, is upregulated in various inflammatory renal diseases and responsible for prostaglandin formation. As prostaglandins are known to influence cell adhesion processes, we investigated the effect of COX-2 inhibition on the expression of α<sub>v</sub> integrins, which are also enhanced in renal diseases and control the adherence between the endothelium and the extracellular matrix (ECM) in the glomerulus. Methods: Healthy female Wistar rats and animals with previously induced passive Heymann nephritis (PHN) received either 5 mg/kg body weight/day celecoxib or a placebo. After 28 days, renal cortical mRNA expression of COX-2 and α<sub>v</sub> integrin subunits was determined. Results: Rats with PHN showed a significant 1.7-fold increase in renal cortical mRNA expression of α<sub>v</sub> integrin subunits. Treatment with celecoxib increased cortical α<sub>v</sub> integrin mRNA expression 2.2-fold (p < 0.05) in healthy animals and 4.0-fold (p < 0.05) in rats with PHN, but lowered COX-2 mRNA expression in rats with PHN to 0.8-fold (p < 0.05). An inverse correlation between the expression of COX-2 and α<sub>v</sub> integrins in rats with PHN was demonstrated. Conclusions: It is suggested that COX-2-derived prostaglandins suppress the expression of α<sub>v</sub> integrins. This implies a previously unknown role for COX-2 in chronic inflammation in the kidney.

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          Most cited references 9

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          Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II.

          Prostaglandins have wide-ranging effects in the body and are thought to be important mediators of inflammation. Cyclooxygenase (COX) plays a key regulatory role in prostaglandin synthesis, and occurs in both constitutive (COX-1) and inducible (COX-2) isoforms. COX-1 is thought to provide cytoprotective effects, whereas COX-2 is both inducible and the major isoform of inflammatory cells. Reduction of prostaglandin production by inhibition of cyclooxygenases appears to be the main mechanism of action of most non-steroidal anti-inflammatory drugs (NSAIDS). Here we present an animal model of COX-2 deficiency that was generated by gene targeting. Defects in null mice correlating with reduced viability included renal alterations, characteristic of renal dysplasia (100% penetrance), and cardiac fibrosis (50% penetrance). Female Cox-2-/- mice were infertile. COX-2 deficiency failed to alter inflammatory responses in several standard models, but striking mitigation of endotoxin-induced hepatocellular cytotoxicity was observed.
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            Cloning two isoforms of rat cyclooxygenase: differential regulation of their expression.

             P Chanmugam,  Y Xia,  L Feng (1993)
            Two isoforms of cyclooxygenase (COX) have been identified in eukaryotic cells: COX-1 encoded by a 2.8-kb mRNA, and a mitogen-inducible COX-2 encoded by a 4-kb mRNA. We have cloned the COX-1 and COX-2 cDNAs from the cDNA library constructed from lipopolysaccharide (LPS)-stimulated rat peritoneal macrophages. The deduced amino acid sequence showed that COX-1 contained 602 amino acids, whereas COX-2 contained 604 amino acids. There is 95% conservation of the nucleotide sequence in the open reading frame of COX-1 between the rat and the mouse, while the homology of the 3' untranslated region is 68% except for a 150 bp segment adjacent to the stop codon which is nonhomologous with the mouse. Transfection of both COX cDNAs into Cos-7 cells resulted in increased COX activity. In rat vascular smooth muscle cells, interleukin-1 beta selectively increased the expression of COX-2, but not that of COX-1, as assessed by enzyme activity, immunoprecipitation of COX proteins, and mRNA analysis. Only the brain among tissues tested exhibits basal expression of COX-2 as the major form of the enzyme. However, COX-2 mRNA was expressed in vivo in the lung and kidney, but not in the heart, after systemic administration of LPS, suggesting that COX-2 but not COX-1 plays a major role in producing COX-derived products of arachidonic acid during endotoxic shock. Thus, the two COX isoforms were differentially expressed, and COX-2 was selectively induced in response to inflammatory stimuli in rats.
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              NSAIDs inhibit alpha V beta 3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis.

               C Ruegg,  O Dormond,  C Paroz (2001)
              Cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, is overexpressed in many cancers. Inhibition of COX-2 by nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of cancer development in humans and suppresses tumor growth in animal models. The anti-cancer effect of NSAIDs seems to involve suppression of tumor angiogenesis, but the underlying mechanism is not completely understood. Integrin alpha V beta 3 is an adhesion receptor critically involved in mediating tumor angiogenesis. Here we show that inhibition of endothelial-cell COX-2 by NSAIDs suppresses alpha V beta 3-dependent activation of the small GTPases Cdc42 and Rac, resulting in inhibition of endothelial-cell spreading and migration in vitro and suppression of fibroblast growth factor-2-induced angiogenesis in vivo. These results establish a novel functional link between COX-2, integrin alpha V beta 3 and Cdc42-/Rac-dependent endothelial-cell migration. Moreover, they provide a rationale to the understanding of the anti-angiogenic activity of NSAIDs.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2003
                February 2003
                17 November 2004
                : 93
                : 2
                : e72-e79
                Affiliations
                aKlinik für Nephrologie und Rheumatologie, und bInstitut für Pharmakologie und Klinische Pharmakologie, Heinrich Heine Universität Düsseldorf, Germany
                Article
                68519 Nephron Exp Nephrol 2003;93:e72–e79
                10.1159/000068519
                12629275
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 6, References: 41, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/68519
                Categories
                Original Paper

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