Eliciting renal failure in mosquitoes

Hematophagous female mosquitoes are vectors of numerous pathogens that threaten the health of humans, livestock, and companion animals.  The primary approach for controlling the spread of these diseases is the spraying of insecticides (e.g., pyrethroids) to kill the vectors.  However, the overuse of such chemicals has led to resistance in mosquitoes.  Thus, new insecticides with novel mechanisms of action are urgently needed for effective mosquito control.  Here we attempt to disrupt a physiological process in mosquitoes that has not yet been targeted by insecticides—i.e., the production of urine by the renal (Malpighian) tubules.  The tubules generate urine by active transepithelial secretion of K⁺, Na⁺, Cl^-, and water from the hemolymph to the tubule lumen.  Inward-rectifying potassium (Kir) channels are hypothesized to mediate one of the major pathways for K⁺ secretion in Malpighian tubules.  Thus, we target these channels in the present study.  We show that a small molecule inhibitor of mammalian Kir channels (VU573) inhibits the activity of at least one mosquito Kir channel (Kir1) expressed in the Malpighian tubules of Aedes aegypti.  Injection of VU573 into adult female mosquitoes incapacitates them within 24 hours and decreases their capacity to survive disruptions to extracellular K⁺ homeostasis.  Moreover, VU573 inhibits the production of urine in isolated Malpighian tubules and the excretion of urine by intact mosquitoes, consistent with our desired mode of action—i.e., renal failure.  Funded by a grant from the Foundation for the NIH, VCTR program.