Piezo2 in bladder-innervating sensory neurons contributes to regulation of contractile activity in cystitis

Overactivity of the urinary bladder constitutes one of the main symptoms in various lower urinary tract disorders and it significantly deteriorates quality of life. The crucial role of mechanotransduction in bladder-innervating unmyelinated C-type primary sensory nerve fibres in initiating the voiding reflex in the overactive bladder has been well established. However, the molecular identity of the mechanotransducer(s) in bladder-innervating C-type sensory neurons is still elusive. The mechanosensitive ion channel Piezo2 in primary sensory neurons has been implicated in various physiological and pathological functions including proprioception, the detection of low and high threshold mechanical stimuli in the skin, and the development of mechanical hypersensitivity in peripheral pathologies. Here, we investigated whether or not Piezo2 expressed in primary sensory neurons could contribute to bladder overactivity in cystitis. Characterisation of Piezo2 expression revealed that about 1/5 of primary sensory neurons express this ion channel and at least half of the Piezo2-expressing cells express various markers for unmyelinated C-type sensory neurons. Further, we found that Piezo2 is expressed predominantly in lamina I and II of the spinal cord, where C-type sensory neurons terminate. We disclosed that Piezo2 is expressed in sensory neuron terminals innervating peripheral tissues including the bladder wall and noxious but not innocuous pressure in the urinary bladder activates Piezo2-expressing primary sensory neurons. Finally, we show that instillation of GsMTx that blocks Piezo2 significantly reduces overactivity in the inflamed but not in the naive urinary bladder. Together these findings indicate that Piezo2 in bladder-innervating unmyelinated C-type neurons contributes to the detection of noxious pressure and regulation of contractile activity in cystitis.