A₁‐Adenosine receptor activation has biphasic roles in development of acute kidney injury at 4 and 24 h of reperfusion following ischaemia in rats

Abstract

New Findings r What is the central question of this study?A 1 -Adenosine receptor (A 1 AR) blockade before renal ischaemia aggravated kidney injury after 24 h reperfusion in several studies, whereas we previously observed a renoprotective effect of A 1 AR blockade during a 4 h reperfusion period. What are the underlying mechanisms for this biphasic effect of pretreatment with an A 1 AR antagonist at 4 and 24 h reperfusion?r What is main finding and its importance?A 1 -Adenosine receptor blockade protects the kidney against ischaemia-induced injury during the early hours of reperfusion by attenuating the reduction in renal blood flow and lowering energy expenditure, whereas its inflammatory effects gradually dominate over 24 h reperfusion to intensify kidney injury.We previously reported that selective blockade of the A 1 -adenosine receptor (A 1 AR) with an antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), had protective effects on renal ischaemia-induced structural and functional disruption during a 4 h reperfusion period. In contrast, several studies demonstrated that endogenous and exogenous A 1 AR activation before renal ischaemia had a renoprotective role 24 h after reperfusion, through mechanisms that reduced inflammation, necrosis and apoptosis. In this study, we investigated potential mechanisms underlying this biphasic action of A 1 AR in renal ischaemia-reperfusion injury. Anaesthetized male Sprague-Dawley rats underwent 30 min of bilateral renal ischaemia, and biphasic effects of pretreatment with DPCPX at 4 and 24 h reperfusion were studied on the kidney injury. Pretreatment with DPCPX attenuated at 4 h but augmented at 24 h reperfusion the renal ischaemia-induced histological damage, reductions in creatinine clearance, urea excretion and free-water reabsorption, and increases in bicarbonate excretion and tissue malondialdehyde. The DPCPX increased tumour necrosis factor-α expression and migration of lymphocytes in the postischaemic kidney at both time points, but with a different pattern; lymphocytes mostly aggregated in cortical periarterial spaces at 4 h reperfusion but had infiltrated into the interstitium at 24 h reperfusion. In conclusion, A 1 AR activation contributes to ischaemia-induced acute kidney injury during the early hours of reperfusion by causing a greater reduction in renal haemodynamics and by elevating tubular energy expenditure, which H. Najafi and others overcome its anti-inflammatory effect. However, its anti-inflammatory actions are exerted by reducing lymphocyte infiltration and cytokine production that begins to dominate from 4 to 24 h of reperfusion, which is reflected in attenuation of renal structural and functional disruption.

Comparison of ischaemia–reperfusion‐induced acute kidney injury by clamping renal arteries, veins or pedicles in anaesthetized rats

“…The renal I/R-induced urine concentrating inability is mainly due to disturbed countercurrent multiplication mechanism by severely damaged TAL and disestablishment of medullary interstitial hyperosmolality Moosavi et al, 2009;Najafi et al 2016), as observed by the indirect index of low urine osmolality in all ischaemic groups in the present study. The fall of U osm by 40%…”

“…It is important to mention that all renal parameters were assessed at 24 h reperfusion in the studies of Park et al and Li et al Recently, we found two different patterns of lymphocyte migration into the kidney following 30 min bilateral renal arterial clamping (Najafi, Owji, Kamali-Sarvestani, & Moosavi, 2016). Lymphocytes mostly aggregated in the cortical periarterial spaces up to 4 h of reperfusion, but then gradually infiltrated the interstitium during 24 h of reperfusion to contribute to intensifying renal injury.…”

“…2003;Najafi et al, 2016). Then, the renal artery and vein on both sides were carefully cleared and separated from each other by using a surgical microscope (SZ2-ET; Olympus Corp., Tokyo, Japan) (Moosavi & Johns.…”

“…After weighing the urine sample and separating plasma, part of them was used for immediate measurement of Na + , K + and osmolality, and the remainder was aliquoted and preserved for later analysis of creatinine, urea and glucose concentration (Najafi et al, 2016). The kidneys were weighed, decapsulated, placed on ice and longitudinally sectioned.…”

“…Then, the renal artery and vein on both sides were carefully cleared and separated from each other by using a surgical microscope (SZ2-ET; Olympus Corp., Tokyo, Japan) (Moosavi & Johns. 2003;Najafi et al, 2016). Both renal arteries in the BIR-A group, veins in the BIR-V group and pedicles in the BIR-P groups were occluded using non-traumatic clamps for 30 min, and blood reflow was confirmed by return of the kidney colour to normal.…”