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• W1964454505 abstract "Kim et al. show that isoflurane uses a tubule-based transforming growth factor-β/CD73-dependent process that generates adenosine to protect mice from ischemic acute kidney injury (AKI) with effects to prevent the ‘no-reflow phenomenon’ and decrease inflammation. While direct cytoprotection occurred in culture, extensive research suggests that in vivo adenosine protection from rodent ischemic AKI is mediated by a mutually cooperative mechanism involving blood flow, inflammation, and innate immunity through multiple adenosine receptors with promiscuous actions on diverse cell types. Kim et al. show that isoflurane uses a tubule-based transforming growth factor-β/CD73-dependent process that generates adenosine to protect mice from ischemic acute kidney injury (AKI) with effects to prevent the ‘no-reflow phenomenon’ and decrease inflammation. While direct cytoprotection occurred in culture, extensive research suggests that in vivo adenosine protection from rodent ischemic AKI is mediated by a mutually cooperative mechanism involving blood flow, inflammation, and innate immunity through multiple adenosine receptors with promiscuous actions on diverse cell types. The clamp model of renal ischemia–reperfusion in rodents is widely used to study ischemic acute kidney injury (AKI). A striking feature of this model is the impact of incomplete reperfusion (the ‘no-reflow phenomenon’) and associated inflammation on injury.1.Timsit M.O. Garcia-Cardena G. Flow-dependent endothelial function and kidney dysfunction.Semin Nephrol. 2012; 32: 185-191Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,2.Laubach V.E. French B.A. Okusa M.D. Targeting of adenosine receptors in ischemia-reperfusion injury.Expert Opin Ther Targets. 2011; 15: 103-118Crossref PubMed Scopus (51) Google Scholar Poor reperfusion resulting from vasoconstriction and capillary damage affects deep cortex and outer medulla, the areas most damaged by ischemia. Stagnation of blood causes endothelial activation, leukocyte adherence, and inflammation.1.Timsit M.O. Garcia-Cardena G. Flow-dependent endothelial function and kidney dysfunction.Semin Nephrol. 2012; 32: 185-191Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Innate immunity, by dendritic cells, T cells, natural killer (NK) and NKT cells, and monocytes, also contributes to inflammation.3.Li L. Okusa M.D. Blocking the immune response in ischemic acute kidney injury: the role of adenosine 2A agonists.Nat Clin Pract Nephrol. 2006; 2: 432-444Crossref PubMed Scopus (57) Google Scholar,4.Rabb H. The promise of immune cell therapy for acute kidney injury.J Clin Invest. 2012; 122: 3852-3854Crossref PubMed Scopus (17) Google Scholar The no-reflow phenomenon becomes manifest soon after clamp release and, if not soon aborted by protective interventions, continues thereafter, with increasing inflammation. Interventions that improve renal blood flow (RBF) or mitigate inflammation markedly reduce AKI severity, raising the question: what are the relative roles of poor reperfusion and inflammation in protection from ischemic AKI? Poor reperfusion and inflammation are intertwined. Poor reperfusion prolongs ischemia beyond clamp release and produces more inflammation, whereas inflammation causes hemodynamic perturbations to decrease RBF. In this chicken-and-egg scenario, poor reperfusion and inflammation are mutually reinforcing to produce more injury; and interventions that either increase RBF or decrease inflammation preemptively mitigate ill effects produced by the other. Within a range of clamp-induced ischemia not too severe, therefore not lethal to the majority of tubules, and not so mild as to produce only sublethal damage, protection by hemodynamic and/or anti-inflammatory interventions is considerable. The window for protection by acute intervention after clamp release is narrow—typically less than 6h—but protection is strikingly complete. These findings suggest that a rapidly developing reperfusion defect and inflammation account for a sizable fraction of subsequent damage distinct and separate from direct effects of the intended durations of clamp ischemia on tubule cells. That is, the no-reflow phenomenon adds significantly to the total ischemic and inflammatory insult beyond that intended by clamping, and cannot be corrected if potentially beneficial interventions are delayed. Furthermore, the diversity of hemodynamic and/or anti-inflammatory interventions that are equivalently protective in rodent clamp ischemia models suggests that underlying mechanisms involve common factors. One such factor may be adenosine, a vasodilatory nucleoside that abolishes the no-reflow phenomenon and ameliorates inflammation to protect rodent kidneys from ischemic AKI.3.Li L. Okusa M.D. Blocking the immune response in ischemic acute kidney injury: the role of adenosine 2A agonists.Nat Clin Pract Nephrol. 2006; 2: 432-444Crossref PubMed Scopus (57) Google Scholar,5.Grenz A. Bauerle J.D. Dalton J.H. et al.Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice.J Clin Invest. 2012; 122: 693-710Crossref PubMed Scopus (94) Google Scholar Kim et al.6.Kim M. Ham A. Kim J.Y. et al.The volatile anesthetic isoflurane induces ecto-5′-nucleotidase (CD73) to protect against renal ischemia and reperfusion injury.Kidney Int. 2013; 84: 90-103Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar (this issue) now report that protection against ischemic AKI by the volatile anesthetic isoflurane is mediated by adenosine (Figure 1). Transforming growth factor-β1 (TGF-β1) generated in tubules by isoflurane induced the expression of epithelial ecto-5′-nucleotidase (CD73) and increased its activity to augment extracellular adenosine. Protection by isoflurane and its mediation by TGF-β required CD73 and functional adenosine receptors. Compared with control pentobarbital, isoflurane prevented RBF decreases in the outer medulla during the first 3h and abrogated cell death and inflammation assessed one day after clamp release. These findings are a significant advance. They provide a credible mechanism to explain flurane anesthetic protection from ischemic AKI and add new dimensions to the complexity of adenosine signaling and its benefits to injury. The observation that TGF-β increases CD73 expression and activity to generate protective adenosine is noteworthy. However, Kim et al. used a nonspecific adenosine receptor antagonist to block adenosine actions,6.Kim M. Ham A. Kim J.Y. et al.The volatile anesthetic isoflurane induces ecto-5′-nucleotidase (CD73) to protect against renal ischemia and reperfusion injury.Kidney Int. 2013; 84: 90-103Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar and we do not know which receptor subtype or subtypes were involved in the protection. The ability of TGF-β to induce CD73 expression on inflammatory cells and immune cells (cited by Kim et al.6.Kim M. Ham A. Kim J.Y. et al.The volatile anesthetic isoflurane induces ecto-5′-nucleotidase (CD73) to protect against renal ischemia and reperfusion injury.Kidney Int. 2013; 84: 90-103Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar) adds more complexity to the interpretation of these results. As discussed below, vascular, inflammatory, and immune cells in addition to tubule epithelium participate in cooperative fashion to produce the component of injury that is sensitive to adenosine-mediated protection. Virtually all cells express adenosine receptors A1, A2A, A2B, and A3 in different permutations. Vasodilatory adenosine increases RBF, through vascular A2 receptors; however, A1 receptors have physiological roles to constrict afferent arterioles during tubuloglomerular feedback.7.Hansen P.B. Hashimoto S. Oppermann M. et al.Vasoconstrictor and vasodilator effects of adenosine in the mouse kidney due to preferential activation of A1 or A2 adenosine receptors.J Pharmacol Exp Ther. 2005; 315: 1150-1157Crossref PubMed Scopus (61) Google Scholar On the other hand, Park et al. reported that A1 receptor activity ameliorates ischemic AKI. They invoked direct cytoprotection of tubule cells through A1 receptor-dependent sphingosine kinase induction, sphingosine-1-phosphate (S1P) production, and S1P1 receptor activation,8.Park S.W. Kim J.Y. Ham A. et al.A1 adenosine receptor allosteric enhancer PD-81723 protects against renal ischemia-reperfusion injury.Am J Physiol Renal Physiol. 2012; 303: F721-F732Crossref PubMed Scopus (32) Google Scholar a mechanism of direct protection of tubule cells by S1P signaling first documented by Bajwa et al.9.Bajwa A. Jo S.K. Ye H. et al.Activation of sphingosine-1-phosphate 1 receptor in the proximal tubule protects against ischemia-reperfusion injury.J Am Soc Nephrol. 2010; 21: 955-965Crossref PubMed Scopus (94) Google Scholar We note, however, that Park et al.8.Park S.W. Kim J.Y. Ham A. et al.A1 adenosine receptor allosteric enhancer PD-81723 protects against renal ischemia-reperfusion injury.Am J Physiol Renal Physiol. 2012; 303: F721-F732Crossref PubMed Scopus (32) Google Scholar assessed acute inflammation but did not measure RBF, an important parameter affected by adenosine. Notably, in their current study, Kim et al. used cultured cells to show that isoflurane–TGF-β–CD73–adenosine protection from ischemic AKI could involve direct cytoprotection of tubules; nevertheless, they also observed remarkable prevention of the no-reflow phenomenon very early during reperfusion.6.Kim M. Ham A. Kim J.Y. et al.The volatile anesthetic isoflurane induces ecto-5′-nucleotidase (CD73) to protect against renal ischemia and reperfusion injury.Kidney Int. 2013; 84: 90-103Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Because the no-reflow phenomenon adds significantly to the total ischemic burden, and its correction is expected to prevent additional tubule damage caused by poor reflow, we cannot be sure of the extent to which direct tubule cytoprotection by isoflurane contributed toward the amelioration of ischemic AKI in their in vivo studies. Thus, uncertainty remains. Unlike protective actions by A1 receptors, studies from Lee’s group suggest also that the activity of A3 adenosine receptors worsens ischemic AKI;10.Lee H.T. Ota-Setlik A. Xu H. et al.A3 adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure.Am J Physiol Renal Physiol. 2003; 284: F267-F273Crossref PubMed Scopus (30) Google Scholar moreover, examination of their role in ischemic injury of other organs has yielded ambiguous results.2.Laubach V.E. French B.A. Okusa M.D. Targeting of adenosine receptors in ischemia-reperfusion injury.Expert Opin Ther Targets. 2011; 15: 103-118Crossref PubMed Scopus (51) Google Scholar Despite these uncertainties regarding A1 and A3 adenosine receptors, there is incontrovertible evidence for protection from ischemic AKI afforded by A2A and A2B receptors located on vascular, inflammatory, and immune cells.2.Laubach V.E. French B.A. Okusa M.D. Targeting of adenosine receptors in ischemia-reperfusion injury.Expert Opin Ther Targets. 2011; 15: 103-118Crossref PubMed Scopus (51) Google Scholar, 3.Li L. Okusa M.D. Blocking the immune response in ischemic acute kidney injury: the role of adenosine 2A agonists.Nat Clin Pract Nephrol. 2006; 2: 432-444Crossref PubMed Scopus (57) Google Scholar, 4.Rabb H. The promise of immune cell therapy for acute kidney injury.J Clin Invest. 2012; 122: 3852-3854Crossref PubMed Scopus (17) Google Scholar, 5.Grenz A. Bauerle J.D. Dalton J.H. et al.Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice.J Clin Invest. 2012; 122: 693-710Crossref PubMed Scopus (94) Google Scholar, 11.Li L. Huang L. Ye H. et al.Dendritic cells tolerized with adenosine A(2)AR agonist attenuate acute kidney injury.J Clin Invest. 2012; 122: 3931-3942Crossref PubMed Scopus (130) Google Scholar, 12.Bauerle J.D. Grenz A. Kim J.H. et al.Adenosine generation and signaling during acute kidney injury.J Am Soc Nephrol. 2011; 22: 14-20Crossref PubMed Scopus (103) Google Scholar The actions of adenosine receptors on RBF and inflammation are so intimately intertwined and their analysis made so confusing by the diversity of adenosine sources in postischemic tissue, and by the ubiquity and promiscuity of receptor expression in renal, inflammatory, and immune cells, that dissection of critical adenosine targets that protect from ischemic AKI is made difficult. Extracellular adenosine after ischemia can be derived from tubules, endothelial and interstitial cells, and inflammatory and immune cells, generated by the conversion of nucleotides to adenosine on cell surfaces by CD39 and CD73, as well as catabolism of adenosine triphosphate (ATP) to adenosine monophosphate (AMP) and adenosine within cells, followed by leakage to extracellular sites where AMP is further converted to adenosine by CD73.2.Laubach V.E. French B.A. Okusa M.D. Targeting of adenosine receptors in ischemia-reperfusion injury.Expert Opin Ther Targets. 2011; 15: 103-118Crossref PubMed Scopus (51) Google Scholar, 12.Bauerle J.D. Grenz A. Kim J.H. et al.Adenosine generation and signaling during acute kidney injury.J Am Soc Nephrol. 2011; 22: 14-20Crossref PubMed Scopus (103) Google Scholar, 13.Weinberg J.M. Venkatachalam M.A. Preserving postischemic reperfusion in the kidney: a role for extracellular adenosine.J Clin Invest. 2012; 122: 493-496Crossref PubMed Scopus (8) Google Scholar Although extracellular adenosine rises, much of it goes back into surviving tubule cells during reperfusion through equilibrative nucleoside transporters (ENTs) and is catabolized or resynthesized to ATP.5.Grenz A. Bauerle J.D. Dalton J.H. et al.Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice.J Clin Invest. 2012; 122: 693-710Crossref PubMed Scopus (94) Google Scholar,13.Weinberg J.M. Venkatachalam M.A. Preserving postischemic reperfusion in the kidney: a role for extracellular adenosine.J Clin Invest. 2012; 122: 493-496Crossref PubMed Scopus (8) Google Scholar A2A receptors are ubiquitously expressed on most inflammatory and immune cells and mediate robust protection from ischemic AKI.2.Laubach V.E. French B.A. Okusa M.D. Targeting of adenosine receptors in ischemia-reperfusion injury.Expert Opin Ther Targets. 2011; 15: 103-118Crossref PubMed Scopus (51) Google Scholar,3.Li L. Okusa M.D. Blocking the immune response in ischemic acute kidney injury: the role of adenosine 2A agonists.Nat Clin Pract Nephrol. 2006; 2: 432-444Crossref PubMed Scopus (57) Google Scholar Interestingly, the quality and quantity of protection afforded by interventions directed at different cell types are similar, suggesting that these several cells of markedly different phenotype—neutrophils, CD4+ T cells, NK and NKT cells, regulatory T cells, and dendritic cells (DCs)—exert their actions in a shared pathway. Known effectors in this pathway include neutrophils and T lymphocytes that transmigrate across walls of stagnant capillaries during poor reperfusion conditions. Early studies established a role for neutrophils.2.Laubach V.E. French B.A. Okusa M.D. Targeting of adenosine receptors in ischemia-reperfusion injury.Expert Opin Ther Targets. 2011; 15: 103-118Crossref PubMed Scopus (51) Google Scholar Studies from the Rabb and Okusa laboratories provided evidence for contributions by native immunity.2.Laubach V.E. French B.A. Okusa M.D. Targeting of adenosine receptors in ischemia-reperfusion injury.Expert Opin Ther Targets. 2011; 15: 103-118Crossref PubMed Scopus (51) Google Scholar, 3.Li L. Okusa M.D. Blocking the immune response in ischemic acute kidney injury: the role of adenosine 2A agonists.Nat Clin Pract Nephrol. 2006; 2: 432-444Crossref PubMed Scopus (57) Google Scholar, 4.Rabb H. The promise of immune cell therapy for acute kidney injury.J Clin Invest. 2012; 122: 3852-3854Crossref PubMed Scopus (17) Google Scholar Most recently, using A2A agonist tolerized DCs, Li et al. tantalizingly showed that DCs have a proximate role in the inflammatory/immune cascade and that conditioned DCs protect by suppressing production of inflammatory cytokines and increasing production of protective cytokines.11.Li L. Huang L. Ye H. et al.Dendritic cells tolerized with adenosine A(2)AR agonist attenuate acute kidney injury.J Clin Invest. 2012; 122: 3931-3942Crossref PubMed Scopus (130) Google Scholar These elegant studies notwithstanding, we are faced with the complexity of endothelial-cell A2A receptors that can mediate nitric oxide-dependent renal vasodilation.7.Hansen P.B. Hashimoto S. Oppermann M. et al.Vasoconstrictor and vasodilator effects of adenosine in the mouse kidney due to preferential activation of A1 or A2 adenosine receptors.J Pharmacol Exp Ther. 2005; 315: 1150-1157Crossref PubMed Scopus (61) Google Scholar Activation of these receptors could abolish the no-reflow phenomenon, reduce total ischemic load, and decrease injury. Therefore, despite incontrovertible adenosine-dependent protection against the ill effects of inflammatory and immune cells shown by knockout/reconstitution studies, adenosine-mediated A2A-dependent protection by improving blood flow also seems plausible. Complicating matters further, Grenz et al. showed prevention of the no-reflow phenomenon and protection from ischemic AKI through activation of low-affinity endothelial A2B receptors under conditions where extracellular adenosine was induced to increase by blockade of proximal tubule equilibrative nucleoside transporter 1 (ENT1).5.Grenz A. Bauerle J.D. Dalton J.H. et al.Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice.J Clin Invest. 2012; 122: 693-710Crossref PubMed Scopus (94) Google Scholar A1, A2A, and A3 knockout mice were similarly protected.5.Grenz A. Bauerle J.D. Dalton J.H. et al.Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice.J Clin Invest. 2012; 122: 693-710Crossref PubMed Scopus (94) Google Scholar,13.Weinberg J.M. Venkatachalam M.A. Preserving postischemic reperfusion in the kidney: a role for extracellular adenosine.J Clin Invest. 2012; 122: 493-496Crossref PubMed Scopus (8) Google Scholar While discrepancies between different adenosine receptor actions can be discussed,2.Laubach V.E. French B.A. Okusa M.D. Targeting of adenosine receptors in ischemia-reperfusion injury.Expert Opin Ther Targets. 2011; 15: 103-118Crossref PubMed Scopus (51) Google Scholar, 12.Bauerle J.D. Grenz A. Kim J.H. et al.Adenosine generation and signaling during acute kidney injury.J Am Soc Nephrol. 2011; 22: 14-20Crossref PubMed Scopus (103) Google Scholar, 13.Weinberg J.M. Venkatachalam M.A. Preserving postischemic reperfusion in the kidney: a role for extracellular adenosine.J Clin Invest. 2012; 122: 493-496Crossref PubMed Scopus (8) Google Scholar it seems to us that during early reperfusion in wild-type mice, there is room for adenosine protection through diverse cellular and receptor targets, and by direct cytoprotection. However, inflammation—and native immunity—and poor reperfusion (the no-reflow phenomenon) appear to affect injury so equivalently and in such closely related manners as to suggest that they cooperatively act in the same mechanism—albeit a complex one—each mutually supportive and required for the common actions of others. A2A receptor occupancy decreases leukocyte adherence in stagnant capillaries and suppresses DC-initiated inflammatory signaling. These effects can improve RBF. On the other hand, A2B (and perhaps A2A) occupancy abrogates the no-reflow phenomenon through vasomotor effects and concomitantly prevents endothelial activation and leukocyte attachment and transmigration by avoiding sluggish blood flow. Joined at the hip, the ill effects of inflammation/immunity and poor perfusion each cannot be without the other. We note that all work to date on adenosine protection from ischemic AKI was done in rodents. This is noteworthy because it has seemed possible that the no-reflow phenomenon may severely affect only the complex vasculature of kidneys with elongated and voluminous renal medullae of animals with high urine-concentrating ability. Riley et al. found no evidence for the no-reflow phenomenon measured by microsphere method as RBF through superficial as well as deep juxtamedullary glomeruli during 60 minutes of reperfusion after 90 minutes’ ischemia in dogs, despite severe functional loss. Measured by flowmeter, RBF was not reduced during 60 minutes’ reperfusion even after 180 minutes’ ischemia of dog kidneys.14.Riley A.L. Alexander E.A. Migdal S. et al.The effect of ischemia on renal blood flow in the dog.Kidney Int. 1975; 7: 27-34Abstract Full Text PDF PubMed Scopus (35) Google Scholar Thus, there are concerns as to whether factors related to reperfusion in a narrow time window after clamp release that add to the total ischemic load in rodent models of ischemic AKI are actually operative and therefore relevant to the pathophysiology of ischemic AKI in large animals, including humans, with simpler medullary vasculature of kidneys and limited concentrating ability.15.Lieberthal W. Nigam S.K. Acute renal failure. II. Experimental models of acute renal failure: imperfect but indispensable.Am J Physiol Renal Physiol. 2000; 278: F1-F12PubMed Google Scholar These considerations are particularly applicable in explaining the disappointing failure of agents such as atrial natriuretic factor and insulin-like growth factor—that have vasoactive effects and afford remarkable protection from ischemic AKI in rodents—to be effective in human AKI trials. It seems possible that ubiquitous adenosine and its actions are common to the mechanisms whereby several diverse agents and interventions protect rodent kidneys from ischemic injury. The availability of sophisticated mouse genetic models with altered adenosine signaling and the proliferation of small molecules with restricted and specific actions on adenosine receptors may augur well for the development of mouse and rat models of ischemic AKI, free of the no-reflow phenomenon postischemia. Examination of AKI developing in such a model may elucidate the effects of ischemia produced by the clamp duration only, uncomplicated by added ischemic burden. Such models may permit investigation of the selective role of inflammation in ischemic AKI, uncomplicated by the no-reflow phenomenon. Is it possible that such models could mimic the behavior of postischemic human kidneys and thus provide practical means of avoiding expensive large-animal studies? We do not know. However, recent findings indicating that human kidneys are more resistant to injury by clamp ischemia than rodent kidneys16.Parekh D.J. Weinberg J.M. Ercole B. et al.Tolerance of the human kidney to isolated controlled ischemia.J Am Soc Nephrol. 2013; 24: 506-517Crossref PubMed Scopus (139) Google Scholar should provide incentive for research into developing animal models of ischemic AKI that more resemble the human." @default.
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• W1964454505 title "The conundrum of protection from AKI by adenosine in rodent clamp ischemia models" @default.
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