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Activation of Adenosine 2A Receptors Preserves Structure and Function of Podocytes

Alaa S. Awad^*,, Michael Rouse^*, Lixia Liu^*, Amy L. Vergis^*, Diane L. Rosin, Joel Linden^*,, John R. Sedor and Mark D. Okusa^*,

Departments of ^* Medicine and Pharmacology and the Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia; and Department of Medicine, Case Western Reserve University, and Rammelkamp Center for Research and Education, MetroHealth System Campus, Cleveland, Ohio

Correspondence: Dr. Mark D. Okusa, Division of Nephrology, Box 133, University of Virginia Health System, Charlottesville, VA 22908. Phone: 434-924-2187; Fax: 434-924-5848; E-mail: mdo7y{at}virginia.edu

Received for publication March 6, 2007. Accepted for publication July 18, 2007.

Adenosine 2A receptor (A_2AR) activation was recently shown to be renoprotective in diabetic nephropathy. A_2AR are found in glomeruli and have been shown to associate with the podocyte cytoskeletal protein -actinin-4, but the effect of their activation on podocyte structure and function is unknown. Podocyte injury was induced in C57BL/6 mice with puromycin aminonucleoside, and the selective A_2AR agonist ATL313 was found to attenuate the resulting albuminuria and foot process fusion. The selective A_2AR antagonist ZM241385 reversed the effects of ATL313. In vitro, A_2AR mRNA and protein were expressed in a conditionally immortalized podocyte cell line, and A_2AR-like immunoreactivity co-localized with the actin cytoskeleton. Treatment with ATL313 also blocked the increased podocyte permeability to albumin and disruption of the actin cytoskeleton that accompanied puromycin aminonucleoside–induced injury in vitro. ATL313 was ineffective, however, in the presence of the A_2AR antagonist and in A_2AR-deficient podocytes. It was concluded that A_2AR activation reduces glomerular proteinuria, at least in part, by preserving the normal structure of podocyte foot processes, slit diaphragms, and actin cytoskeleton.

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