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Published ahead of print on September 24, 2008
J Am Soc Nephrol 19: 2375-2383, 2008
© 2008 American Society of Nephrology
doi: 10.1681/ASN.2008010035
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BASIC RESEARCH

Zag Expression during Aging Suppresses Proliferation after Kidney Injury

Roland Schmitt*,{dagger}, Arnaud Marlier* and Lloyd G. Cantley*

* Section of Nephrology, Department of Medicine, Yale University, New Haven, Connecticut; and {dagger} Department of Nephrology, Hannover Medical School, Hannover, Germany

Correspondence: Dr. Roland Schmitt, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Phone: +49-511-60060418; Fax: +49-511-552366; E-mail: schmitt.roland{at}mh-hannover.de; or Dr. Lloyd G. Cantley, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208029, New Haven, CT 06510. Phone: 203-785-7110; Fax: 203-785-4904; E-mail: lloyd.cantley{at}yale.edu

Received for publication January 11, 2008. Accepted for publication June 26, 2008.

Recovery after acute kidney injury is impaired in the elderly, but mechanistic information regarding why this occurs is limited. In this study, aged mouse kidneys displayed a reduced epithelial proliferative reserve in vivo and in vitro. Microarray analysis identified increased expression of zinc-{alpha} (2)-glycoprotein (Zag) in aged proximal tubular cells. The addition of recombinant Zag to primary renal epithelial cell cultures decreased proliferation, whereas knockdown of Zag increased proliferation. In vivo, systemic small interference RNA suppressed expression of Zag in the mouse proximal tubule; this increased the rate of epithelial cell proliferation after renal ischemia/reperfusion in aged mice but also increased parenchymal fibrosis. These results demonstrate that increased Zag expression in the aged kidney acts to suppress the proliferative response to injury and introduce Zag as a modifier of the aging phenotype.






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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673