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Renal arterial infusion of tempol prevents medullary hypoperfusion,hypoxia, and acute kidney injury in ovine Gram-negative sepsis |
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| Authors: | Ashenafi H Betrie Shuai Ma Connie P C Ow Rachel M Peiris Roger G Evans Scott Ayton Darius J R Lane Adam Southon Simon R Bailey Rinaldo Bellomo Clive N May Yugeesh R Lankadeva |
| Institution: | 1. Preclinical Critical Care Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia
Translational Neurodegeneration Laboratory, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia;2. Preclinical Critical Care Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China;3. Preclinical Critical Care Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia;4. Translational Neurodegeneration Laboratory, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia;5. Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Melbourne, Victoria, Australia;6. Department of Critical Care, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia Department of Intensive Care, Royal Melbourne Hospital, Melbourne, Victoria, Australia |
| Abstract: | AimRenal medullary hypoperfusion and hypoxia precede acute kidney injury (AKI) in ovine sepsis. Oxidative/nitrosative stress, inflammation, and impaired nitric oxide generation may contribute to such pathophysiology. We tested whether the antioxidant and anti-inflammatory drug, tempol, may modify these responses.MethodsFollowing unilateral nephrectomy, we inserted renal arterial catheters and laser-Doppler/oxygen-sensing probes in the renal cortex and medulla. Noanesthetized sheep were administered intravenous (IV) Escherichia coli and, at sepsis onset, IV tempol (IVT; 30 mg kg−1 h−1), renal arterial tempol (RAT; 3 mg kg−1 h−1), or vehicle.ResultsSeptic sheep receiving vehicle developed renal medullary hypoperfusion (76 ± 16% decrease in perfusion), hypoxia (70 ± 13% decrease in oxygenation), and AKI (87 ± 8% decrease in creatinine clearance) with similar changes during IVT. However, RAT preserved medullary perfusion (1072 ± 307 to 1005 ± 271 units), oxygenation (46 ± 8 to 43 ± 6 mmHg), and creatinine clearance (61 ± 10 to 66 ± 20 mL min−1). Plasma, renal medullary, and cortical tissue malonaldehyde and medullary 3-nitrotyrosine decreased significantly with sepsis but were unaffected by IVT or RAT. Consistent with decreased oxidative/nitrosative stress markers, cortical and medullary nuclear factor-erythroid-related factor-2 increased significantly and were unaffected by IVT or RAT. However, RAT prevented sepsis-induced overexpression of cortical tissue tumor necrosis factor alpha (TNF-α; 51 ± 16% decrease; p = 0.003) and medullary Thr-495 phosphorylation of endothelial nitric oxide synthase (eNOS; 63 ± 18% decrease; p = 0.015).ConclusionsIn ovine Gram-negative sepsis, renal arterial infusion of tempol prevented renal medullary hypoperfusion and hypoxia and AKI and decreased TNF-α expression and uncoupling of eNOS. However, it did not affect markers of oxidative/nitrosative stress, which were significantly decreased by Gram-negative sepsis. |
| Keywords: | acute kidney injury hypoxia inflammation nitric oxide synthase renal microcirculation sepsis |