Renal arterial infusion of tempol prevents medullary hypoperfusion, hypoxia, and acute kidney injury in ovine Gram-negative sepsis
© 2023 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society..
AIM: Renal 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.
METHODS: Following 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.
RESULTS: Septic 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).
CONCLUSIONS: In 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:239 |
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| Enthalten in: |
Acta physiologica (Oxford, England) - 239(2023), 1 vom: 20. Sept., Seite e14025 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Betrie, Ashenafi H [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.08.2023 Date Revised 05.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/apha.14025 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Betrie, Ashenafi H |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Renal arterial infusion of tempol prevents medullary hypoperfusion, hypoxia, and acute kidney injury in ovine Gram-negative sepsis |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 28.08.2023 | ||
| 500 | |a Date Revised 05.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society. | ||
| 520 | |a AIM: Renal 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 | ||
| 520 | |a METHODS: Following 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 | ||
| 520 | |a RESULTS: Septic 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) | ||
| 520 | |a CONCLUSIONS: In 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a acute kidney injury | |
| 650 | 4 | |a hypoxia | |
| 650 | 4 | |a inflammation | |
| 650 | 4 | |a nitric oxide synthase | |
| 650 | 4 | |a renal microcirculation | |
| 650 | 4 | |a sepsis | |
| 650 | 7 | |a tempol |2 NLM | |
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| 650 | 7 | |a Tumor Necrosis Factor-alpha |2 NLM | |
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| 700 | 1 | |a Ma, Shuai |e verfasserin |4 aut | |
| 700 | 1 | |a Ow, Connie P C |e verfasserin |4 aut | |
| 700 | 1 | |a Peiris, Rachel M |e verfasserin |4 aut | |
| 700 | 1 | |a Evans, Roger G |e verfasserin |4 aut | |
| 700 | 1 | |a Ayton, Scott |e verfasserin |4 aut | |
| 700 | 1 | |a Lane, Darius J R |e verfasserin |4 aut | |
| 700 | 1 | |a Southon, Adam |e verfasserin |4 aut | |
| 700 | 1 | |a Bailey, Simon R |e verfasserin |4 aut | |
| 700 | 1 | |a Bellomo, Rinaldo |e verfasserin |4 aut | |
| 700 | 1 | |a May, Clive N |e verfasserin |4 aut | |
| 700 | 1 | |a Lankadeva, Yugeesh R |e verfasserin |4 aut | |
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