title: The volatile anesthetic isoflurane induces ecto-5'-nucleotidase (CD73) to protect against renal ischemia and reperfusion injury.
abstract: The volatile anesthetic isoflurane protects against renal ischemia and reperfusion injury by releasing renal tubular TGF-β1. As adenosine is a powerful cytoprotective molecule, we tested whether TGF-β1 generated by isoflurane induces renal tubular ecto-5'-nucleotidase (CD73) and adenosine to protect against renal ischemia and reperfusion injury. Isoflurane induced new CD73 synthesis and increased adenosine generation in cultured kidney proximal tubule cells and in mouse kidney. Moreover, a TGF-β1-neutralizing antibody prevented isoflurane-mediated induction of CD73 activity. Mice anesthetized with isoflurane after renal ischemia and reperfusion had significantly reduced plasma creatinine and decreased renal tubular necrosis, neutrophil infiltration, and apoptosis compared with pentobarbital-anesthetized mice. Isoflurane failed to protect against renal ischemia and reperfusion injury in CD73-deficient mice, in mice pretreated with a selective CD73 inhibitor, or in mice treated with an adenosine receptor antagonist. The TGF-β1-neutralizing antibody or the CD73 inhibitor attenuated isoflurane-mediated protection against HK-2 cell apoptosis. Thus, isoflurane causes TGF-β1-dependent induction of renal tubular CD73 and adenosine generation to protect against renal ischemia and reperfusion injury. Modulation of this pathway may have important therapeutic implications to reduce morbidity and mortality arising from ischemic acute kidney injury.
authors: Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, Anesthesiology Research Laboratories, Columbia University, New York, New York, USA.
authors: Mihwa
authors: M
authors: Kim
authors: Ahrom
authors: A
authors: Ham
authors: Joo Y
authors: JY
authors: Kim
authors: Kevin M
authors: KM
authors: Brown
authors: Vivette D
authors: VD
authors: D'Agati
authors: H Thomas
authors: HT
authors: Lee
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D058186:Acute Kidney Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000241:Adenosine / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D020556:Neutrophil Infiltration / Q000187:drug effects; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014835:Volatilization
chemical_list: D018685:Anesthetics, Inhalation; D057134:Antibodies, Neutralizing; D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D058915:Purinergic P1 Receptor Antagonists; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D007530:Isoflurane; D015720:5'-Nucleotidase; C548241:NT5E protein, human; C548242:Nt5e protein, mouse; D000241:Adenosine