• Natarajan Aravindan, Mohan Natarajan, and Andrew D Shaw.
• Division of Anesthesiology and Critical Care, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. naravind@mdanderson.org
• J. Cardiothorac. Vasc. Anesth. 2006 Apr 1; 20 (2): 179-86.

ObjectiveVasoactive compounds are known to modulate gene transcription, including nuclear factor kappa B (NF-kappaB), in renal tissues, but the molecular effects of fenoldopam in this setting are not known. The authors used a rat model of surgical acute ischemic nephropathy to test the hypothesis that fenoldopam attenuates ischemia/reperfusion (I/R)-induced NF-kappaB-mediated inflammation.DesignProspective, single-blind, randomized, controlled animal study.SettingAcademic Department of Anesthesiology laboratory.SubjectsTwenty-four male Sprague-Dawley rats.InterventionsRats were anesthetized by intraperitoneal administration of 50 mg/kg of urethane and randomly allocated into 4 groups (n = 6 each): sham operation, sham operation with infusion of 0.1 microg/kg/min of fenoldopam, unilateral renal ischemia (1 hour, left renal artery cross-clamping) followed by 4 hours of reperfusion, and unilateral renal I/R with fenoldopam infusion.Measurements And Main ResultsKidney samples were used to measure NF-kappaB DNA-binding activity with an electrophoretic mobility shift assay. NF-kappaB signaling-dependent gene transcription was assessed with microarray analysis, and validated with reverse transcriptase polymerase chain reaction (RT-PCR). Expression of insulin-like growth factor-1 and nitric oxide synthetase-3 messenger RNA (not included in the array) was studied with RT-PCR. NF-kappaB DNA binding activity was significantly higher (p < 0.001) after I/R injury. Of the 96 genes analyzed, 75 were induced and another 8 were suppressed completely (2-fold or greater change v control) after I/R. Treatment with fenoldopam prevented activation of NF-kappaB DNA binding activity (p < 0.001) and attenuated 72 of 75 I/R-induced genes and 3 of 8 I/R-suppressed genes.ConclusionData from this rat model of renal I/R suggest that the mechanism by which fenoldopam attenuates I/R-induced inflammation appears to involve inhibition of NF-kappaB translocation and signal transduction.

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