Lower urinary tract symptoms (LUTS) are prevalent among the aging population, and current medications offer limited efficacy. Improved therapies require a better understanding of the mechanisms underlying LUTS. Abnormal extracellular ATP levels and altered purinergic contractility have been reported in patients with LUTS, suggesting dysregulation of the purinergic pathways. CD39/ENTPD1 is a major regulator of purinergic metabolism, and patients with ENTPD1 loss-of-function mutations exhibit bladder hypomotility and incontinence, suggesting critical roles for ENTPD1 in bladder function. We have tested this hypothesis in an overexpression mouse model with human ENTPD1 knock-in (hCD39TG), in a hemizygous Entpd1 mouse model (Entpd1+/-) mimicking LUTS patients with impaired ATP hydrolysis, and in a homozygous Entpd1-deleted mouse model (Entpd1-/-) mimicking the complete ENTPD1 loss-of-function observed in patients. We have demonstrated that ENTPD1 dysregulation leads to profound abnormalities in bladder voiding phenotypes and urodynamics, along with impaired BSM contractility and altered purinergic receptor signaling. Furthermore, we have found that modulation of downstream P2Y12/adenosine A2b receptor signaling partially or fully restores normal bladder function. Finally, we have identified expression of ENTPD1 and associated purinergic proteins in human BSM cells, underscoring the critical role of ENTPD1 in human bladder function and highlighting its translational potential for the treatment of LUTS.
