Research Article: The Reno-Vascular A2B Adenosine Receptor Protects the Kidney from Ischemia

Date Published: June 24, 2008

Publisher: Public Library of Science

Author(s): Almut Grenz, Hartmut Osswald, Tobias Eckle, Dan Yang, Hua Zhang, Zung Vu Tran, Karin Klingel, Katya Ravid, Holger K Eltzschig, Neil Turner

Abstract: BackgroundAcute renal failure from ischemia significantly contributes to morbidity and mortality in clinical settings, and strategies to improve renal resistance to ischemia are urgently needed. Here, we identified a novel pathway of renal protection from ischemia using ischemic preconditioning (IP).Methods and FindingsFor this purpose, we utilized a recently developed model of renal ischemia and IP via a hanging weight system that allows repeated and atraumatic occlusion of the renal artery in mice, followed by measurements of specific parameters or renal functions. Studies in gene-targeted mice for each individual adenosine receptor (AR) confirmed renal protection by IP in A1−/−, A2A−/−, or A3AR−/− mice. In contrast, protection from ischemia was abolished in A2BAR−/− mice. This protection was associated with corresponding changes in tissue inflammation and nitric oxide production. In accordance, the A2BAR-antagonist PSB1115 blocked renal protection by IP, while treatment with the selective A2BAR-agonist BAY 60–6583 dramatically improved renal function and histology following ischemia alone. Using an A2BAR-reporter model, we found exclusive expression of A2BARs within the reno-vasculature. Studies using A2BAR bone-marrow chimera conferred kidney protection selectively to renal A2BARs.ConclusionsThese results identify the A2BAR as a novel therapeutic target for providing potent protection from renal ischemia.

Partial Text: Acute renal failure is defined as a rapid decrease in the glomerular filtration rate (GFR), occurring over a period of minutes to days [1]. The causes of acute renal failure are classically divided into three categories, prerenal, postrenal, or intrinsic [1]. However, over 50% of hospitalized patients with acute renal failure suffer from renal ischemia leading to prerenal azotemia or “intrinsic” acute tubular necrosis [2]. In fact, a recent study of hospitalized patients revealed that only a mild increase in the serum creatinine level (0.3–0.4 mg/dl) is associated with a 70% greater risk of death than in persons without any increase [3]. Along these lines, surgical procedures requiring cross-clamping of the aorta and renal vessels are associated with a renal failure rate of up to 30% [4]. Similarly, acute renal failure after cardiac surgery occurs in up to 10% of patients under normal circumstances and is associated with dramatic increases in mortality [5]. Taken together, these data highlight the urgent need for additional therapeutic modalities to prevent renal injury from ischemia [6–8].

In the present study, we investigated endogenous pathways for renal protection from ischemia. For this purpose, we utilized a recently developed model of renal IP via isolated renal artery occlusion by use of a hanging weight system, which allows for highly reproducible renal injury [40]. While previous studies on IP in the heart have focused on histological measurements of myocardial cell death or leakage of myocardial specific enzymes into the systemic circulation, this model allowed us to assess the consequences of IP-treatment on the preservation of specific renal functions, such as GFR, urinary sodium or potassium excretion, or urine production. On the basis of previous work showing extracellular adenosine generation in renal protection from ischemia [19,20], we tested the contribution of signaling through individual ARs to renal protection from ischemia by IP. Using genetic and pharmacological approaches, these studies revealed a pivotal role of the A2BAR. In fact, selective A2BAR agonist treatment provided a similar degree of renal protection from ischemia as IP treatment itself, suggesting that A2BAR agonists “precondition” the kidneys. Finally, the use of a reporter mouse model and studies in bone marrow A2BAR chimera helped to pinpoint the source of A2BAR protection to the reno-vasculature. This vascular phenotype was a surprising finding, as previous studies in the heart have conferred preconditioning phenomena mainly towards a metabolic adaptation of the myocardium [27,28,35,36,57]. In contrast, the present studies have revealed a critical contribution of the reno-vascular A2BAR to renal IP protection. Taken together, these data provide what we believe to be a previously not appreciated role of reno-vascular A2BAR signaling in enhancing renal resistance to ischemia and provide strong rationale for therapeutically targeting the A2BAR during renal ischemia.



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