Adenosine kinase inhibition protects against cisplatin-induced nephrotoxicity

Area of Science:

• Nephrology
• Pharmacology
• Molecular Biology

Background:

• Cisplatin chemotherapy causes kidney damage through oxidative stress, DNA damage, and inflammation.
• Adenosine is a protective molecule in inflammation, and its receptors offer renal protection but have side effects.
• Adenosine kinase (ADK) regulates adenosine levels; its inhibition is explored for therapeutic potential.

Purpose of the Study:

• To investigate the potential of inhibiting adenosine kinase (ADK) to mitigate cisplatin-induced nephrotoxicity.
• To determine the role of adenosine receptors in the protective effects of ADK inhibition against kidney injury.

Main Methods:

• Pretreatment with the ADK inhibitor ABT-702 in vivo and in HK2 cells.
• Assessment of cisplatin-induced acute kidney injury, tubular cell apoptosis, oxidative stress, and inflammation.
• Evaluation of the effects of adenosine receptor antagonists (A1, A2B, A2A, A3) on ADK inhibition's protective effects.

Main Results:

• ADK inhibition with ABT-702 significantly reduced cisplatin-induced kidney injury, apoptosis, oxidative stress, and inflammation.
• Inhibition of ADK suppressed apoptosis, reactive oxygen species, and inflammation in HK2 cells.
• The protective effect was dependent on A1 and A2B adenosine receptors and modulated by A2A and A3 receptors.

Conclusions:

• Inhibiting ADK increases extracellular adenosine, offering protection against cisplatin nephrotoxicity.
• The protective mechanism involves reducing oxidative stress and inflammation via A1 and A2B adenosine receptors.
• Targeting ADK presents a potential therapeutic strategy for preventing cisplatin-induced kidney damage.