Protective role of ecto-5'-nucleotidase (CD73) in renal ischemia.
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.
Grenz
Almut
A
Department of Pharmacology and Toxicology, Tübingen University Hospital, Tübingen, Germany.
Zhang
Hua
H
Eckle
Tobias
T
Mittelbronn
Michel
M
Wehrmann
Manfred
M
Köhle
Christoph
C
Kloor
Doris
D
Thompson
Linda F
LF
Osswald
Hartmut
H
Eltzschig
Holger K
HK
D015720:5'-Nucleotidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058186:Acute Kidney Injury / Q000209:etiology / Q000517:prevention & control*; D000241:Adenosine / Q000096:biosynthesis*; D000818:Animals; D004195:Disease Models, Animal; D007511:Ischemia / Q000150:complications / Q000378:metabolism*; D019194:Ischemic Preconditioning; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D015720:5'-Nucleotidase; D000241:Adenosine