Renal arterial infusion of tempol prevents medullary hypoperfusion, hypoxia, and acute kidney injury in ovine Gram‐negative sepsis

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.

Current insights into the Pathophysiology of kidney diseases

“…The question arises but remains as to whether therapy with tempol could be of benefit in the case of established septic AKI. 3 Exercise training is another strategy to prevent sepsisassociated organ dysfunction. Physical exercise upregulates the expression of muscle-derived R-spondin 3 (RSPO3), a secreted protein that showed a beneficial effect in murine models of mesenteric ischemia/ reperfusion injury and lung injury.…”

“…However, renal arterial infusion of tempol prevented the onset of renal medullary hypoperfusion and hypoxia and thereby the development of AKI in septic sheep over 24 h. Oxidative and nitrosative stress markers were not affected, suggesting that oxidative stress displays no precondition to AKI development in ovine sepsis. The question arises but remains as to whether therapy with tempol could be of benefit in the case of established septic AKI 3 …”

Recent advances in kidney research

“…Sepsis was also a topic of a work by Betrie et al 4 . Here the researchers investigated how the drug tempol acts on the kidney during ovine Gram‐negative sepsis.…”

“…Sepsis was also a topic of a work by Betrie et al 4 Here the researchers investigated how the drug tempol acts on the kidney during ovine Gram-negative sepsis. Tempol is used as an antioxidant and anti-inflammatory drug in this study.…”