Adenosine 2A receptor (A2AR) activation was recently shown to be renoprotective in diabetic nephropathy. A2AR are found in glomeruli and have been shown to associate with the podocyte cytoskeletal protein α-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 A2AR agonist ATL313 was found to attenuate the resulting albuminuria and foot process fusion. The selective A2AR antagonist ZM241385 reversed the effects of ATL313. In vitro, A2AR mRNA and protein were expressed in a conditionally immortalized podocyte cell line, and A2AR-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 A2AR antagonist and in A2AR-deficient podocytes. It was concluded that A2AR activation reduces glomerular proteinuria, at least in part, by preserving the normal structure of podocyte foot processes, slit diaphragms, and actin cytoskeleton.
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