Activation of adenosine 2A receptors preserves structure and function of podocytes

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 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 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.