Fenoldopam inhibits nuclear translocation of nuclear factor kappa B in a rat model of surgical ischemic acute renal failure

Objective: Vasoactive compounds are known to modulate gene transcription, including nuclear factor kappa B (NF-kappa B), 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-kappa B-mediated inflammation. Design: Prospective, single-blind, randomized, controlled animal study. Setting: Academic Department of Anesthesiology laboratory. Subjects: Twenty-four male Sprague-Dawley rats. Interventions: Rats 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 mu g/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 fenoldoparn infusion. Measurements and Main Results: Kidney samples were used to measure NF-kappa B DNA-binding activity with an electrophoretic mobility shift assay. NF-kappa B 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-kappa B 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-kappa B DNA binding activity (p < 0.001) and attenuated 72 of 75 I/R-induced genes and 3 of 8 I/R-suppressed genes. Conclusion: Data from this rat model of renal I/R suggest that the mechanism by which fenoldoparn attenuates I/R-induced inflammation appears to involve inhibition of NF-kappa B translocation and signal transduction. (c) 2006 Elsevier Inc. All rights reserved.