Identification of the molecular pathways that drive constitutive renal COX‐2 expression: implications for novel COX‐2‐targetted therapies that spare the cardiovascular system (837.9)

Autor: Jane A. Mitchell, John L. Wallace, Jing Jiao, Maria F. Gomez, Melissa V. Chan, Lisa Berglund, Nicholas S. Kirkby, Anne K. Zaiss, Harvey R. Herschman, Eliana Garcia-Vaz
Rok vydání: 2014
Předmět:
Zdroj: The FASEB Journal. 28
ISSN: 1530-6860
0892-6638
Popis: Drugs such as diclofenac and celecoxib inhibit cyclo-oxygenase (COX)-2 to produce anti-inflammatory benefit, but also produce renal/cardiovascular toxicity by inhibition of constitutive COX-2 in the kidney. During inflammation COX-2 is rapidly induced by well-defined pathways including nuclear factor κB (NFκB) and nuclear factor of activated T-cells (NFAT) but it is not known if these also drive physiological renal expression of COX-2. To explore this we compared the distribution of constitutive COX-2 expression with constitutive NFκB and NFAT activity using luciferase reporter mice. COX-2 was highly expressed in the medulla of the kidney. This closely matched a ‘hotspot’ of constitutive NFAT activity but did not correlate with NFκB activity (Figure A). To determine if constitutive renal COX-2 was driven by this NFAT activity we treated mice with cyclosporine A (CsA) to inhibit calcineurin-dependent NFAT activation. CsA reduced constitutive COX-2 expression in the renal medulla but had no effect on endoto...
Databáze: OpenAIRE
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