Fenoldopam Inhibits Nuclear Translocation of Nuclear Factor Kappa B in a Rat Model of Surgical Ischemic Acute Renal Failure

• Published in: Journal of cardiothoracic and vascular anesthesia Vol. 20; no. 2; pp. 179 - 186
• Main Authors: Aravindan, Natarajan, Natarajan, Mohan, Shaw, Andrew D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2006
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - etiology; Acute Kidney Injury - metabolism; acute renal failure; Animals; Disease Models, Animal; DNA - genetics; fenoldopam; Fenoldopam - administration & dosage; Follow-Up Studies; Gene Expression - drug effects; inflammation; Infusions, Intravenous; Insulin-Like Growth Factor I - genetics; Ischemia - complications; Ischemia - drug therapy; Ischemia - metabolism; ischemia/reperfusion injury; Kidney - blood supply; Male; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB; Nitric Oxide Synthase Type III - genetics; Postoperative Complications; Prospective Studies; rat kidney; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - drug effects; Transcription, Genetic - genetics; Vasodilator Agents - administration & dosage; rat kidney; NF-κB; acute renal failure; inflammation; ischemia/reperfusion injury; fenoldopam
• ISSN: 1053-0770; 1532-8422
• DOI: 10.1053/j.jvca.2005.03.028

Objective: Vasoactive compounds are known to modulate gene transcription, including nuclear factor kappa B (NF-κB), 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-κB-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 μg/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 Results: Kidney samples were used to measure NF-κB DNA-binding activity with an electrophoretic mobility shift assay. NF-κB 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-κB 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-κB 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 fenoldopam attenuates I/R-induced inflammation appears to involve inhibition of NF-κB translocation and signal transduction.