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

Natarajan Aravindan, Mohan Natarajan, Andrew D. Shaw

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)179-186
Number of pages8
JournalJournal of Cardiothoracic and Vascular Anesthesia
Volume20
Issue number2
DOIs
StatePublished - Apr 2006

Fingerprint

Fenoldopam
Anatomic Models
NF-kappa B
Acute Kidney Injury
Reperfusion
Ischemia
Kidney
Genes
Reverse Transcriptase Polymerase Chain Reaction
DNA
Inflammation
Anesthesiology
Urethane
Electrophoretic Mobility Shift Assay
Somatomedins
Renal Artery
Microarray Analysis
Reperfusion Injury
Constriction
Nitric Oxide Synthase

Keywords

  • acute renal failure
  • fenoldopam
  • inflammation
  • ischemia/reperfusion injury
  • NF-κB
  • rat kidney

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Fenoldopam Inhibits Nuclear Translocation of Nuclear Factor Kappa B in a Rat Model of Surgical Ischemic Acute Renal Failure. / Aravindan, Natarajan; Natarajan, Mohan; Shaw, Andrew D.

In: Journal of Cardiothoracic and Vascular Anesthesia, Vol. 20, No. 2, 04.2006, p. 179-186.

Research output: Contribution to journalArticle

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abstract = "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.",
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N2 - 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.

AB - 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.

KW - acute renal failure

KW - fenoldopam

KW - inflammation

KW - ischemia/reperfusion injury

KW - NF-κB

KW - rat kidney

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