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

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.

Unilateral nephrectomy diminishes ischemic acute kidney injury through enhanced perfusion and reduced pro-inflammatory and pro-fibrotic responses

“…Each animal underwent either right UNx or sham UNx, and was subjected to either 37 minutes of unilateral renal ischemia by left renal artery clamping or sham operation [ 30 ]. All operations were of similar total length.…”

“…First, the right-sided nephrectomy or sham procedure was performed. Next, the left renal artery was carefully dissected, and a non-traumatic microvascular clamp was used to occlude the artery to induce 37 minutes of warm ischemia [ 30 ]. The sham ischemia procedure involved visual identification of the left renal hilus.…”

Zinc Supplementation and Ischemia Pre-conditioning in Renal Ischemia/Reperfusion Injury

“…It is also expected that the RIR injury induced inflammation may increase KW as Afyouni and colleagues demonstrated that KW increased in RIR injury model (19). A model of IPC, in which bilateral renal pedicles were clipped for 5 min followed by 5 min reperfusion for three times, resulted in an improvement of renal injury (20). Such improvement was not obtained in our experiment.…”

Subclinical effects of remote ischaemic conditioning in human kidney transplants revealed by quantitative proteomics

“…Also, proteomic analysis of plasma in RIC models found measureable changes of the acute inflammatory response [ 11 , 12 ]. At the same time, mixed results have been observed, revealing no difference in levels of tubular damage caused by IRI after combined or separate pre- and post-conditioning [ 6 , 13 , 14 ]. More recently, the results of a randomised clinical trial in kidney transplantation (CONTEXT) were reported, applying RIC (preconditioning) to recipients of deceased donor kidneys.…”