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No Effect of Remote Ischemic Conditioning Strategies on Recovery from Renal Ischemia-Reperfusion Injury and Protective Molecular Mediators.

Kierulf-Lassen C, Kristensen ML, Birn H, Jespersen B, Nørregaard R - PLoS ONE (2015)

Bottom Line: Kidney function recovery was associated with a significant up-regulation of phosphorylated protein kinase B (pAkt), extracellular regulated kinase 1/2 (pERK1/2), and heat shock proteins (HSPs) pHSP27, HSP32, and HSP70, but rIC was not associated with any significant differences in tubular damage, inflammatory, or fibrosis marker expression.In our study, rIC did not protect the kidney against IRI.This was associated with pAkt and pERK1/2 up-regulation and increased HSP expression at day 7.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

ABSTRACT
Ischemia-reperfusion injury (IRI) is the major cause of acute kidney injury. Remote ischemic conditioning (rIC) performed as brief intermittent sub-lethal ischemia and reperfusion episodes in a distant organ may protect the kidney against IRI. Here we investigated the renal effects of rIC applied either prior to (remote ischemic preconditioning; rIPC) or during (remote ischemic perconditioning; rIPerC) sustained ischemic kidney injury in rats. The effects were evaluated as differences in creatinine clearance (CrCl) rate, tissue tubular damage marker expression, and potential kidney recovery mediators. One week after undergoing right-sided nephrectomy, rats were randomly divided into four groups: sham (n = 7), ischemia and reperfusion (IR; n = 10), IR+rIPC (n = 10), and IR+rIPerC (n = 10). The rIC was performed as four repeated episodes of 5-minute clamping of the infrarenal aorta followed by 5-minute release either before or during 37 minutes of left renal artery clamping representing the IRI. Urine and blood were sampled prior to ischemia as well as 3 and 7 days after reperfusion. The kidney was harvested for mRNA and protein isolation. Seven days after IRI, the CrCl change from baseline values was similar in the IR (δ: 0.74 mL/min/kg [-0.45 to 1.94]), IR+rIPC (δ: 0.21 mL/min/kg [-0.75 to 1.17], p > 0.9999), and IR+rIPerC (δ: 0.41 mL/min/kg [-0.43 to 1.25], p > 0.9999) groups. Kidney function recovery was associated with a significant up-regulation of phosphorylated protein kinase B (pAkt), extracellular regulated kinase 1/2 (pERK1/2), and heat shock proteins (HSPs) pHSP27, HSP32, and HSP70, but rIC was not associated with any significant differences in tubular damage, inflammatory, or fibrosis marker expression. In our study, rIC did not protect the kidney against IRI. However, on days 3-7 after IRI, all groups recovered renal function. This was associated with pAkt and pERK1/2 up-regulation and increased HSP expression at day 7.

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The study design and the four experimental groups.A) All animals underwent right nephrectomy 7–8 days prior to the renal ischemia-reperfusion injury or sham operation. Urinary creatinine clearance was determined prior to renal ischemia-reperfusion (IR; termed baseline) and days 3 and 7 post-operatively. B) The remote ischemic conditioning stimulus was applied as four cycles of 5 minutes of ischemia and 5 minutes of reperfusion by clamping the infrarenal aorta either before (remote ischemic preconditioning; rIPC) or during (remote ischemic perconditioning; rIPerC) 37 minutes of unilateral renal ischemia.
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pone.0146109.g001: The study design and the four experimental groups.A) All animals underwent right nephrectomy 7–8 days prior to the renal ischemia-reperfusion injury or sham operation. Urinary creatinine clearance was determined prior to renal ischemia-reperfusion (IR; termed baseline) and days 3 and 7 post-operatively. B) The remote ischemic conditioning stimulus was applied as four cycles of 5 minutes of ischemia and 5 minutes of reperfusion by clamping the infrarenal aorta either before (remote ischemic preconditioning; rIPC) or during (remote ischemic perconditioning; rIPerC) 37 minutes of unilateral renal ischemia.

Mentions: All animals underwent right nephrectomy 7–8 days prior to the renal IRI or sham operation. The rats were then randomised into the following groups: sham (n = 7), IR (n = 10), IR+rIPC (n = 10), and IR+rIPerC (n = 10). The randomization took place in the morning of each day prior to ischemia or sham operation, i.e. 7–8 days after the unilateral nephrectomy procedure. The animals were individually randomized, and allocated to the different treatment groups by drawing lots. In order to avoid day-to-day variations in perioperative conditions to result in any systematic differences in the groups, we also used block randomization. Each day all 3–4 groups were represented in the drawing pool in a number proportionate to their final group size. The sequence of the animals was determined by the order in which they were drawn. No further measures of randomization were found to be feasible during the rest of the experiments. The study was not blinded.The IR, IR+rIPC, and IR+rIPerC groups were subjected to 37 minutes of warm renal ischemia by clamping of the left renal artery. Urine was collected for 24 hours in metabolic cages before (defined as baseline) as well as 2 and 6 days after the IRI (Fig 1A). Ethylenediaminetetraacetic acid (EDTA)-treated blood was sampled at the end of each urine collection period: i.e. baseline and at days 3 and 7. The primary outcome, i.e. urinary creatinine clearance (CrCl) rate, was calculated as 24-hour urine creatinine excretion divided by plasma creatinine (pCr). The rats were allowed to acclimate in the metabolic cages 24 hours prior to the actual urine collection periods except at the end of the study. The rIC stimulus was induced using a 4×5+5–minute IR protocol: i.e. 5 minutes of ischemia followed by 5 minutes of reperfusion repeated four times either prior to (IR+rIPC group) or during (IR+rIPerC) IRI (Fig 1B). The rIC was applied by infrarenal aorta clamping above the bifurcation. Pilot studies were performed to establish an appropriate ischemia time (30, 37, or 45 minutes) based on the increase in pCr and survival. A choice of 37 minutes of ischemia was chosen based on survival with the maximum decline in renal function.


No Effect of Remote Ischemic Conditioning Strategies on Recovery from Renal Ischemia-Reperfusion Injury and Protective Molecular Mediators.

Kierulf-Lassen C, Kristensen ML, Birn H, Jespersen B, Nørregaard R - PLoS ONE (2015)

The study design and the four experimental groups.A) All animals underwent right nephrectomy 7–8 days prior to the renal ischemia-reperfusion injury or sham operation. Urinary creatinine clearance was determined prior to renal ischemia-reperfusion (IR; termed baseline) and days 3 and 7 post-operatively. B) The remote ischemic conditioning stimulus was applied as four cycles of 5 minutes of ischemia and 5 minutes of reperfusion by clamping the infrarenal aorta either before (remote ischemic preconditioning; rIPC) or during (remote ischemic perconditioning; rIPerC) 37 minutes of unilateral renal ischemia.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697851&req=5

pone.0146109.g001: The study design and the four experimental groups.A) All animals underwent right nephrectomy 7–8 days prior to the renal ischemia-reperfusion injury or sham operation. Urinary creatinine clearance was determined prior to renal ischemia-reperfusion (IR; termed baseline) and days 3 and 7 post-operatively. B) The remote ischemic conditioning stimulus was applied as four cycles of 5 minutes of ischemia and 5 minutes of reperfusion by clamping the infrarenal aorta either before (remote ischemic preconditioning; rIPC) or during (remote ischemic perconditioning; rIPerC) 37 minutes of unilateral renal ischemia.
Mentions: All animals underwent right nephrectomy 7–8 days prior to the renal IRI or sham operation. The rats were then randomised into the following groups: sham (n = 7), IR (n = 10), IR+rIPC (n = 10), and IR+rIPerC (n = 10). The randomization took place in the morning of each day prior to ischemia or sham operation, i.e. 7–8 days after the unilateral nephrectomy procedure. The animals were individually randomized, and allocated to the different treatment groups by drawing lots. In order to avoid day-to-day variations in perioperative conditions to result in any systematic differences in the groups, we also used block randomization. Each day all 3–4 groups were represented in the drawing pool in a number proportionate to their final group size. The sequence of the animals was determined by the order in which they were drawn. No further measures of randomization were found to be feasible during the rest of the experiments. The study was not blinded.The IR, IR+rIPC, and IR+rIPerC groups were subjected to 37 minutes of warm renal ischemia by clamping of the left renal artery. Urine was collected for 24 hours in metabolic cages before (defined as baseline) as well as 2 and 6 days after the IRI (Fig 1A). Ethylenediaminetetraacetic acid (EDTA)-treated blood was sampled at the end of each urine collection period: i.e. baseline and at days 3 and 7. The primary outcome, i.e. urinary creatinine clearance (CrCl) rate, was calculated as 24-hour urine creatinine excretion divided by plasma creatinine (pCr). The rats were allowed to acclimate in the metabolic cages 24 hours prior to the actual urine collection periods except at the end of the study. The rIC stimulus was induced using a 4×5+5–minute IR protocol: i.e. 5 minutes of ischemia followed by 5 minutes of reperfusion repeated four times either prior to (IR+rIPC group) or during (IR+rIPerC) IRI (Fig 1B). The rIC was applied by infrarenal aorta clamping above the bifurcation. Pilot studies were performed to establish an appropriate ischemia time (30, 37, or 45 minutes) based on the increase in pCr and survival. A choice of 37 minutes of ischemia was chosen based on survival with the maximum decline in renal function.

Bottom Line: Kidney function recovery was associated with a significant up-regulation of phosphorylated protein kinase B (pAkt), extracellular regulated kinase 1/2 (pERK1/2), and heat shock proteins (HSPs) pHSP27, HSP32, and HSP70, but rIC was not associated with any significant differences in tubular damage, inflammatory, or fibrosis marker expression.In our study, rIC did not protect the kidney against IRI.This was associated with pAkt and pERK1/2 up-regulation and increased HSP expression at day 7.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

ABSTRACT
Ischemia-reperfusion injury (IRI) is the major cause of acute kidney injury. Remote ischemic conditioning (rIC) performed as brief intermittent sub-lethal ischemia and reperfusion episodes in a distant organ may protect the kidney against IRI. Here we investigated the renal effects of rIC applied either prior to (remote ischemic preconditioning; rIPC) or during (remote ischemic perconditioning; rIPerC) sustained ischemic kidney injury in rats. The effects were evaluated as differences in creatinine clearance (CrCl) rate, tissue tubular damage marker expression, and potential kidney recovery mediators. One week after undergoing right-sided nephrectomy, rats were randomly divided into four groups: sham (n = 7), ischemia and reperfusion (IR; n = 10), IR+rIPC (n = 10), and IR+rIPerC (n = 10). The rIC was performed as four repeated episodes of 5-minute clamping of the infrarenal aorta followed by 5-minute release either before or during 37 minutes of left renal artery clamping representing the IRI. Urine and blood were sampled prior to ischemia as well as 3 and 7 days after reperfusion. The kidney was harvested for mRNA and protein isolation. Seven days after IRI, the CrCl change from baseline values was similar in the IR (δ: 0.74 mL/min/kg [-0.45 to 1.94]), IR+rIPC (δ: 0.21 mL/min/kg [-0.75 to 1.17], p > 0.9999), and IR+rIPerC (δ: 0.41 mL/min/kg [-0.43 to 1.25], p > 0.9999) groups. Kidney function recovery was associated with a significant up-regulation of phosphorylated protein kinase B (pAkt), extracellular regulated kinase 1/2 (pERK1/2), and heat shock proteins (HSPs) pHSP27, HSP32, and HSP70, but rIC was not associated with any significant differences in tubular damage, inflammatory, or fibrosis marker expression. In our study, rIC did not protect the kidney against IRI. However, on days 3-7 after IRI, all groups recovered renal function. This was associated with pAkt and pERK1/2 up-regulation and increased HSP expression at day 7.

Show MeSH
Related in: MedlinePlus