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-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.


METHODS
Prospective, single-blind, randomized, controlled animal study.


METHODS
Academic Department of Anesthesiology laboratory.


METHODS
Twenty-four male Sprague-Dawley rats.


METHODS
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 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.


RESULTS
Kidney 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.


CONCLUSIONS
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-kappaB translocation and signal transduction.
Aravindan
Natarajan
N
Division of Anesthesiology and Critical Care, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. naravind@mdanderson.org
Natarajan
Mohan
M
Shaw
Andrew D
AD
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000818:Animals; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D018818:Fenoldopam / Q000008:administration & dosage*; D005500:Follow-Up Studies; D015870:Gene Expression / Q000187:drug effects; D007262:Infusions, Intravenous; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D007511:Ischemia / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D007668:Kidney / Q000098:blood supply*; D008297:Male; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D011183:Postoperative Complications; D011446:Prospective Studies; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000235:genetics*; D014665:Vasodilator Agents / Q000008:administration & dosage
D016328:NF-kappa B; D014665:Vasodilator Agents; D007334:Insulin-Like Growth Factor I; D004247:DNA; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D018818:Fenoldopam