Inwardly rectifying potassium channels mediate polymyxin-induced nephrotoxicity

Area of Science:

• Nephrology
• Pharmacology
• Molecular Biology

Background:

• Polymyxins are crucial last-line antibiotics against Gram-negative bacteria.
• Polymyxin-induced nephrotoxicity limits their clinical use.
• Understanding polymyxin toxicity mechanisms is vital for safer drug development.

Purpose of the Study:

• To identify genetic factors contributing to polymyxin-induced kidney toxicity.
• To elucidate the molecular mechanisms underlying polymyxin nephrotoxicity.
• To explore therapeutic strategies for mitigating polymyxin toxicity.

Main Methods:

• Whole-genome CRISPR screen in human kidney HK-2 cells.
• Molecular dynamics simulations of polymyxin B1 interaction with Kir4.2.
• Assessment of cell viability and membrane potential changes.
• Inhibition studies using Kir channel blockers (BaCl2, VU0134992).

Main Results:

• Identified 86 genes whose knockout rescued polymyxin toxicity.
• Knockout of Kir4.2 and Kir5.1 channels significantly reduced polymyxin toxicity and cell depolarization.
• Polymyxin B1 binds to Kir4.2, increasing channel opening and potassium influx.
• Kir channel inhibitors decreased polymyxin toxicity in cell culture and kidney explants.

Conclusions:

• Kir4.2 and Kir5.1 channels mediate polymyxin-induced nephrotoxicity through cell depolarization and increased drug uptake.
• Targeting Kir channels offers a promising strategy to reduce polymyxin-induced kidney damage.
• These findings pave the way for developing safer polymyxin formulations.