A1 adenosine receptor knockout mice are protected against acute radiocontrast nephropathy in vivo

The role of renal A(1) adenosine receptors (A(1)AR) in the pathogenesis of radiocontrast nephropathy is controversial. We aimed to further elucidate the role of A(1)AR in the pathogenesis of radiocontrast nephropathy and determine whether renal proximal tubule A(1)AR contribute to the radiocontrast nephropathy. To induce radiocontrast nephropathy, A(1)AR wild-type (WT) or knockout (KO) mice were injected with a nonionic radiocontrast (iohexol, 1.5-3 g iodine/kg). Some A(1)WT mice were pretreated with 8-cyclopentyl-1,3-dipropylxanthine ( DPCPX; a selective A(1)AR antagonist) before iohexol injection. A(1)AR contribute to the pathogenesis of radiocontrast nephropathy in vivo as the A(1)WT mice developed significantly worse acute renal failure, more renal cortex vacuolization, and had lower survival 24 h after iohexol treatment compared with the A(1)KO mice. DPCPX pretreatment also protected the A(1)WT mice against radiocontrast-induced acute renal failure. No differences in renal cortical apoptosis or inflammation were observed between A(1)WT and A(1)KO mice. To determine whether the proximal tubular A(1)AR mediate the direct renal cytotoxicity of radiocontrast, we treated proximal tubules in culture with iohexol with or without 2-chloro-N-6-cyclopentyladenosine (a selective A(1)AR agonist) or DPCPX pretreatment. We also subjected cultured proximal tubule cells overexpressing A(1)AR or lacking A(1)AR to radiocontrast injury. Iohexol caused a direct dose-dependent reduction in proximal tubule cell viability as well as proliferation. Neither the A(1)AR agonist nor the antagonist treatment affected proximal tubule viability or proliferation. Moreover, overexpression or lack of A(1)AR failed to impact the iohexol toxicity on proximal tubule cells. Therefore, we conclude that radiocontrast causes acute renal failure via mechanisms dependent on A(1)AR; however, renal proximal tubule A(1)AR do not contribute to the direct tubular toxicity of radiocontrast.