Adenosine kinase inhibition protects against cisplatin-induced nephrotoxicity.

Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely linked to cisplatin-induced nephrotoxicity. Adenosine, emerging as a key regulatory molecule, is mostly protective in the pathophysiology of inflammatory diseases. A previous study showed that some of the adenosine receptors led to renal protection against ischemia-reperfusion injury. However, these adenosine receptor agonists lack a useful therapeutic index due to cardiovascular side effects. We hypothesized that inhibition of adenosine kinase (ADK) might exacerbate extracellular adenosine levels to reduce cisplatin-induced renal injury. In the present study, pretreatment with the ADK inhibitor ABT-702 could markedly attenuate cisplatin-induced acute kidney injury, tubular cell apoptosis, oxidative stress, and inflammation in the kidneys. Consistent with in vivo results, inhibition of ADK suppressed cisplatin-induced apoptosis, reactive oxygen species production, and inflammation in HK2 cells. Additionally, the protective effect of ADK inhibition was abolished by A1 or A2B adenosine receptor antagonist and enhanced by A2A or A3 adenosine receptor antagonist. Collectively, the results suggest that inhibition of ADK might increase extracellular adenosine levels, which inhibited cisplatin-induced oxidative stress and inflammation via A1 and A2B adenosine receptors, finally suppressing cisplatin-induced cell apoptosis. Pharmacological therapies based on ADK will be of potential use in therapy of cisplatin-induced nephrotoxicity.