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

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

doi:10.1111/apha.14025

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

Acta Physiol (Oxf). 2023 Sep;239(1):e14025. doi: 10.1111/apha.14025. Epub 2023 Aug 7.

Authors

Ashenafi H Betrie^{1

2}, Shuai Ma^{1

3}, Connie P C Ow¹, Rachel M Peiris¹, Roger G Evans^{1

4}, Scott Ayton², Darius J R Lane², Adam Southon², Simon R Bailey⁵, Rinaldo Bellomo^{6

7

8

9}, Clive N May^{1

6}, Yugeesh R Lankadeva^{1

6}

Affiliations

¹ Preclinical Critical Care Unit, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
² Translational Neurodegeneration Laboratory, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
³ Division of Nephrology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁴ Biomedicine Discovery Institute and Department of Physiology, Monash University, 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.
⁷ Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia.
⁸ Department of Intensive Care, Austin Hospital, Melbourne, Victoria, Australia.
⁹ Department of Intensive Care, Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Abstract

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.

Keywords: acute kidney injury; hypoxia; inflammation; nitric oxide synthase; renal microcirculation; sepsis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury* / metabolism
Animals
Creatinine
Escherichia coli
Hypoxia / metabolism
Kidney / metabolism
Renal Circulation / physiology
Sepsis* / metabolism
Sheep
Tumor Necrosis Factor-alpha

Substances

tempol
Tumor Necrosis Factor-alpha
Creatinine