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Published ahead of print on January 31, 2007
J Am Soc Nephrol 18: 833-845, 2007
© 2007 American Society of Nephrology
doi: 10.1681/ASN.2006101141
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Pathophysiology of Renal Disease and Progression

Protective Role of Ecto-5'-Nucleotidase (CD73) in Renal Ischemia

Almut Grenz*, Hua Zhang*, Tobias Eckle{dagger}, Michel Mittelbronn{ddagger}, Manfred Wehrmann§, Christoph Köhle*, Doris Kloor*, Linda F. Thompson||, Hartmut Osswald* and Holger K. Eltzschig{dagger}

Departments of * Pharmacology and Toxicology and {dagger} Anesthesiology and Intensive Care Medicine, {ddagger} Institute of Brain Research, § Department of Pathology, Tübingen University Hospital, Tübingen, Germany; and || Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma

Address correspondence to: Dr. Holger K. Eltzschig, Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Zentrum für Medizinische Forschung, Waldhörnle Strasse. 22, D-72072 Tübingen, Germany. Phone: +49-7071-2981137; Fax: +49-7071-294416; E-mail: heltzschig{at}partners.org; or Dr. Hartmut Osswald, Department of Pharmacology and Toxicology, Tübingen University Hospital, Wilhelmstrasse 56, D-72074 Tübingen, Germany. Phone: +49-7071-2972268; Fax: +49-7071-294942; E-mail: hartmut.osswald{at}uni-tuebingen.de

Received for publication October 23, 2006. Accepted for publication December 19, 2006.

Acute renal failure from ischemia significantly contributes to cardiovascular morbidity and mortality. Extracellular adenosine has been implicated as an anti-inflammatory metabolite particularly during conditions of limited oxygen availability (e.g., ischemia). Because ecto-5'-nucleotidase (CD73) is rate limiting for extracellular adenosine generation, this study examined the contribution of CD73-dependent adenosine production to ischemic preconditioning (IP) of the kidneys. After the initial observation that murine CD73 transcript, protein, and function are induced by renal IP, its role in IP-mediated kidney protection was studied. In fact, increases in renal adenosine concentration with IP are attenuated in cd73–/– mice. Moreover, pharmacologic inhibition of CD73 or its targeted gene deletion abolished renal protection by IP as measured by clearance studies, plasma electrolytes, and renal tubular destruction, and reconstitution of cd73–/– mice with soluble 5'-nucleotidase resulted in complete restoration of renal protection by IP. Finally, renal injury after ischemia was attenuated by intraperitoneal treatment of wild-type mice with soluble 5'-nucleotidase to a similar degree as by IP. Taken together, these data reveal what is believed to be a previously unrecognized role of CD73 in renal protection from ischemia and suggest treatment with soluble 5'-nucleotidase as a novel therapeutic approach in the treatment of renal diseases that are precipitated by limited oxygen availability.




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