These findings suggest that endogenous activation of A(1)-AR contributes to the early development of renal ischaemia/reperfusion injury.

Animal models of ischaemic acute kidney injury (AKI) are valuable tools, but their therapeutic outcomes are not usually translated to humans. Ischaemic AKI in murines is mostly induced via renal pedicle clamping, which is different from patients with AKI that is due to renal artery hypoperfusion or vein thrombosis. This study was designed to compare the traditional pedicle-clamping with artery or vein occlusion alone in rat models of bilateral renal ischaemia-reperfusion (BIR). Twenty-eight anaesthetized male Sprague-Dawley rats were divided into four groups, a sham-operation group and groups that underwent 2 h reperfusion following 30 min clamping of renal arteries (BIR-A group), veins (BIR-V group) or pedicles (BIR-P group). The levels of epithelial injury in proximal tubules and thick ascending limb, intratubular casts and vascular congestion as well as renal malondialdehyde were moderately lower in the BIR-A than BIR-P group, while the BIR-V group showed much higher degrees of these damages than both these groups along with massive haemorrhagic congestion. Accordingly, renal blood flow, glomerular filtration, Na reabsorption, K and urea excretion, free water reabsorption and urine osmolality were lower in the BIR-V group than in the BIR-A and BIR-P groups, while the BIR-P group had slightly worse renal functional disorders than the BIR-A group. It seems that transmission of high arterial pressure into renal microvessels during venous occlusion causes rupture of capillary walls and haemorrhagic congestion, which leads to intensive kidney injury. In conclusion, the differences in renal disturbances induced by artery, vein and pedicle clamping strongly suggest use of a proper experimental model for each type of human ischaemic AKI.

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.

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