Functional roles for PIEZO1 and PIEZO2 in urothelial mechanotransduction and lower urinary tract interoception

Abstract

The mechanisms that link visceral mechanosensation to the perception of internal organ status (i.e., interoception) remain elusive. In response to bladder filling, the urothelium releases ATP, which is hypothesized to stimulate voiding function by communicating the degree of bladder fullness to subjacent tissues including afferent nerve fibers. To determine if PIEZO channels function as mechanosensors in these events, we generated conditional urothelial Piezo1-, Piezo2-, and dual Piezo1/2-knockout (KO) mice. While functional PIEZO1 channels were expressed in all urothelial cell layers, Piezo1-KO mice had a limited phenotype. Piezo2 expression was limited to a small subset of superficial umbrella cells, yet male Piezo2-KO mice exhibited incontinence (i.e., leakage) when their voiding behavior was monitored during their active dark phase. Dual Piezo1/2-KO mice had the most significant phenotype, characterized by decreased urothelial responses to mechanical stimulation, diminished ATP release, bladder hypoactivity in anesthetized Piezo1/2-KO females, but not male ones, and urinary incontinence in both male and female Piezo1/2-KO mice during their dark phase, but not inactive light one. Our studies reveal that the urothelium functions in a sex and circadian manner to link urothelial PIEZO1/2 channeldriven mechanotransduction to normal voiding function and behavior, and in the absence of these signals, bladder dysfunction ensues.

Myeloid Piezo1 Deletion Protects Renal Fibrosis by Restraining Macrophage Infiltration and Activation

“…A previous report has suggested that Piezo1 is present in a range of inherent urinary cells in the kidney, including epithelium and interstitial cells, using Piezo1-tdTomato reporter mice. 28 Piezo1 functions in epithelial cells by regulating urine osmolarity 29 and sensing intrarenal pressure. 30 A recent study has revealed that Piezo1 alleviates UUO-induced renal fibrosis by increasing p38/MAPK-YAP (p38/mitogen-activated protein kinase-Yes-associated protein) activity.…”

Bladder infection with uropathogenic Escherichia coli increases the excitability of afferent neurons

“…To evaluate micturition in awake, freely moving mice, we used a modified version of the standard void spot assay that incorporates video monitoring as we have recently described (60,61). The system consists of an upper compartment, which housed two mouse cages side by side, each made of acrylic sheets with a ultraviolet-transmitting acrylic bottom (dimensions of 37 Â 25 Â 20 cm), and a lower compartment, which houses ultraviolet tube lights (model T8-F20BLB24, 24 in., ADJ).…”

“…Voiding events were identified by visual inspection of the movies. The void spot area was computed from video images using ImageJ Fiji, as we have previously described (60,62). The parameters evaluated in this study were the number of voids per hour and urine volume per void (in μL).…”

“…Urinary urgency and frequency as well as pain in the lower pelvic area are cardinal symptoms of UTI (3,15,48). Voiding function in awake control mice or those inoculated with UTI89 was evaluated using a recently described video-monitored void spot assay (60,61). Control mice exhibited a characteristic voiding pattern with large voids on the edge of the cage (Fig.…”

Male Lower Urinary Tract Dysfunction: An Underrepresented Endpoint in Toxicology Research

“…There is still uncertainty about how the bladder relays the perception of fullness to the brain. One possibility is that mechanoreceptors and mechanosensitive ion channels within the bladder transmit information about fullness to afferent neurons [52][53][54][55][56]. There is also evidence that urothelial cells, stretched during bladder filling, release ATP to activate purinergic receptors on bladder afferents and relay bladder fullness to the brain [57][58][59].…”