Male Akita mice develop signs of bladder underactivity independent of NLRP3 as a result of a decrease in neurotransmitter release from efferent neurons.

Diabetic Bladder Dysfunction (DBD) is a prevalent diabetic complication that is recalcitrant to glucose control. Using the Akita mouse model (type 1) bred to be NLRP3 or NLRP3, we previously found that females (mild hyperglycemia) progress from an overactive to an underactive bladder phenotype and this progression was dependent on NLRP3-induced inflammation. Here we examined DBD in the male Akita (severe hyperglycemia) and found by urodynamics only a compensated underactive-like phenotype (increased void volume and decreased frequency but unchanged efficiency). Surprisingly, this phenotype was still present in the NLRP3 strain and so was not dependent on NLRP3 inflammasome-induced inflammation. Examining the cause of the compensated underactive-like phenotype, we assessed overall nerve density and afferent nerves (Aδ-fibers). Both were decreased in density during diabetes but denervation was absent in the diabetic NLRP3 strain so it was deemed unlikely to cause the underactive-like symptoms. Changes in bladder smooth muscle (BSM) contractility to cell depolarization and receptor activation were also not responsible as KCl (depolarizing agent), carbachol (muscarinic agonist) and α, β-methylene-ATP (purinergic agonist) elicited equivalent contractions in denuded bladder strips in all groups. However, electrical field stimulation revealed a diabetes-induced decrease in contractility that was not blocked in the NLRP3 strains suggesting that bladder compensated underactive-like phenotype in the male Akita is likely through a decrease in efferent neurotransmitter release.