Biphasic actions of the adenosine A2a receptor antagonist istradefylline in mice with obstructive uropathy

Regardless of its underlying causes, progressive chronic kidney disease is characterized by progressive kidney fibrosis. The adenosine A2a receptor is expressed by activated kidney fibroblasts. Istradefylline is an adenosine A2a receptor antagonist that has received regulatory authority approval as add-on treatment of Parkinson's disease. Here, we examined the potential of repurposing istradefylline for kidney disease by administering istradefylline to mice with kidney fibrosis caused by unilateral ureteral obstruction (UUO). C57BL/6N mice underwent sham or UUO surgery and were followed for 14 days. Mice were treated with vehicle or istradefylline, with istradefylline initiated either the day after surgery (early intervention) or seven days after surgery (late intervention). Early intervention with istradefylline increased mortality in UUO mice and upregulated the expression of some inflammatory genes. In contrast, late intervention with istradefylline attenuated upregulation of the profibrotic cytokine Il11 and of extracellular matrix proteins in UUO kidneys. Istradefylline similarly attenuated transforming growth factor-β1 induced upregulation of Il11, Col1a1 and Fn1 in NRK-49F fibroblasts. The adenosine A2a receptor has both anti-inflammatory and profibrotic effects. The therapeutic window by which adenosine A2a receptor antagonism may slow CKD progression is thus relatively narrow, even when employing an agent with immediate clinical applicability.