Scavenging reactive oxygen species using tempol in the acute phase of renal ischemia/reperfusion and its effects on kidney oxygenation and nitric oxide levels

Aksu, Uğur; Ergin, Bülent; Bezemer, Rick; Kandil, Aslı; Milstein, Dan M.J.; Demirci-Tansel, Cihan; İnce, Can

doi:10.1186/s40635-015-0057-y

Cited by 27 publications

(45 citation statements)

References 33 publications

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“…Although not confirmed experimentally, this effect is likely related to the superoxide scavenging properties of TEMPOL, as a result of which hydrogen peroxide production and corollary NF-κB activation [79,80] and thus iNOS hyperactivation and NO overproduction are suppressed. Our parallel study with suprarenal artery clamping as a model for I/R AKI [58] demonstrated a considerable drop in renal NO levels at 90 min reperfusion (reflecting an increase in peroxynitrite formation). The intrarenal NO concentration was restored to pre-I/R levels by TEMPOL pretreatment in that model, implying that peroxynitrite formation was blocked due to reduced superoxide production.…”

Section: Tempol Reduces I/r-induced Renal Inos and Il-6 Expressionmentioning

confidence: 79%

“…To validate our I/R AKI model and the pharmacodynamic effects of TEMPOL in juxtaposition to the results obtained in literature and our parallel study with renal artery occlusion [58], the degree of iNOS expression, oxidative stress, kidney damage, and inflammation were analyzed first in rats subjected to 30 min of renal ischemia followed by 90 min of reperfusion. This I/R regimen has been standardly employed as a model for AKI [68,69].…”

Section: Characterization and Validation Of The Ischemia/reperfusion mentioning

confidence: 87%

“…In the second group ('Ctrl + TEMPOL'), rats underwent a sham operation and were administered TEMPOL at 200 μmol/kg/h during 105 min. This dose was validated in our previous study [58]. In the third group ('I/R'), the animals underwent a 30-min aortic crossclamping (just below the superior mesenteric artery), rendering both kidneys ischemic, followed by 90 min of reperfusion.…”

Section: Experimental Protocolmentioning

confidence: 99%

“…It should be noted that urine-based kidney function parameters (urine production, creatinine clearance rate / glomerular filtration rate, and renal sodium reabsorption [58]) could not be determined because of I/R-induced anuria in all groups.…”

Section: Blood Gas Acid-base Balance and Lactate Analysis From Bloomentioning

confidence: 99%

“…Conversely, relatively little information is available in terms of renal oxygenation, which is critical for renal function [8]. In a study that was conducted in parallel to the work presented here [58], the protective effects of TEMPOL on (micro)vascular hemodynamics and oxygenation were demonstrated in a setting of renal I/R induced by renal artery clamping (30 min ischemia, 90 min reperfusion). However, this procedure is not representative for the clinical situation where AKI is mainly induced by aortic clamping [4], affecting more than just the kidneys.…”

Section: Introductionmentioning

confidence: 95%

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TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping

Ergin

Bezemer

Kandil

et al. 2015

JCTRes

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Background: Renal ischemia-reperfusion (I/R) is a common clinical complication in critically ill patients that is associated with considerable morbidity and mortality. Renal I/R is a major cause of acute kidney injury (AKI) resulting from I/R-induced oxidative stress, sterile inflammation, and microcirculatory perfusion defects, which can be ameliorated with the superoxide scavenger TEMPOL. The most common cause of AKI in the clinical setting is aortic surgery with suprarenal aortic clamping. The protective effect of TEMPOL in aortic clamping-induced renal I/R has not been studied before. Aim: To evaluate the protective effects of TEMPOL on oxidative stress, inflammation, tissue injury, and renal hemodynamics and oxygenation in a clinically representative rat model of I/R using aortic crossclamping. Methods: Animals (N = 24) were either sham-operated or subjected to ischemia (30 min) and 90-min reperfusion, with or without TEMPOL treatment (15 min before ischemia and during entire reperfusion phase, 200 μmol/kg/h). Systemic and renal hemodynamics, renal oxygenation, and blood gas values were determined at 15 min and 90 min of reperfusion. At 90-min reperfusion, iNOS, inflammation (IL-6, MPO), oxidative stress (MDA), and tissue damage (NGAL, L-FABP) were determined in tissue biopsies. Results: TEMPOL administration at a cumulative dose of 400 μmol/kg conferred a protective effect on AKI in terms of reducing renal damage, inflammation, and iNOS activation. With respect to renal hemodynamics and oxygenation, TEMPOL only reduced renal vascular resistance to near-baseline levels at both reperfusion time points and partially ameliorated the I/R-induced drop microvascular partial tension of oxygen at 90 min reperfusion. Also, TEMPOL alleviated the I/R-induced metabolic acidosis. However, TEMPOL exerted no restorative effect in terms of the severely reduced mean arterial pressure, renal blood flow, and renal oxygen delivery and consumption. The renal oxygen extraction ratio remained unchanged during the 90-min reperfusion phase. Kidneys in all groups were anuric throughout the experiment. Conclusions: This clinically representative renal I/R model, which entails both renal I/R and hind limb I/R as opposed to the standardly used renal I/R model that employs renal artery clamping, resulted in relatively moderate direct AKI. The damage was exacerbated by the perturbed systemic hemodynamics and metabolic acidosis as a result of the hind limb I/R. TEMPOL partially intervened in the factors that led to AKI as well as renal microvascular partial tension of oxygen and metabolic acidosis. However, more effective interventions should be devised for the mean arterial pressure drop (i.e., anuria) associated with aortic clamping and for restoring other critical renal hemodynamic and oxygenation parameters in order to improve post-I/R renal function. Relevance for patients: TEMPOL is a promising compound that has been shown to protect kidneys from I/R damage, which is relevant in kidney transplantation, pancreas transplantation, and ...

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Section: Tempol Reduces I/r-induced Renal Inos and Il-6 Expressionmentioning

confidence: 79%

Section: Characterization and Validation Of The Ischemia/reperfusion mentioning

confidence: 87%

Section: Experimental Protocolmentioning

confidence: 99%

Section: Blood Gas Acid-base Balance and Lactate Analysis From Bloomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

See 3 more Smart Citations

TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping

Ergin

Bezemer

Kandil

et al. 2015

JCTRes

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Nitroxides in Disease

Likhtenshtein

2020

Nitroxides

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Perinatal α-tocopherol overload programs alterations in kidney development and renal angiotensin II signaling pathways at birth and at juvenile age: Mechanisms underlying the development of elevated blood pressure

Ribeiro

Cabral

Vieira‐Filho

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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α-Tocopherol (α-Toc) overload increases the risk of dying in humans (E.R. Miller III et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality Ann Int Med. 142 (2005) 37-46), and overload during early development leads to elevation of blood pressure at adult life, but the mechanism(s) remains unknown. We hypothesized that α-Toc overload during organogenesis affects the renal renin angiotensin system (RAS) components and renal Na handling, culminating with late elevated blood pressure. Pregnant Wistar rats received α-Toc or the superoxide dismutase mimetic tempol throughout pregnancy. We evaluated components of the intrarenal renin angiotensin system in neonate and juvenile offspring: Ang II-positive cells, Ang II receptors (AT and AT), linked protein kinases, O production, NADPH oxidase abundance, lipid peroxidation and activity of Na-transporting ATPases. In juvenile offspring we followed the evolution of arterial blood pressure. Neonates from α-Toc and tempol mothers presented with accentuated retardment in tubular development, pronounced decrease in glomerular Ang II-positive cells and AT/AT ratio, intense production of O and upregulation of the α, ε and λ PKC isoforms. α-Toc decreased or augmented the abundance of renal (Na+K)ATPase depending on the age and α-Toc dose. In juvenile rats the number of Ang II-positive cells returned to control values as well as PKCα, but co-existing with marked upregulation in the activity of (Na+K) and Na-ATPase and elevated arterial pressure at 30 days. We conclude that the mechanisms of these alterations rely on selective targeting of renal RAS components through genic and pro-oxidant effects of the vitamin.

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Scavenging reactive oxygen species using tempol in the acute phase of renal ischemia/reperfusion and its effects on kidney oxygenation and nitric oxide levels

Cited by 27 publications

References 33 publications

TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping

TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping

Nitroxides in Disease

Perinatal α-tocopherol overload programs alterations in kidney development and renal angiotensin II signaling pathways at birth and at juvenile age: Mechanisms underlying the development of elevated blood pressure

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