Vezina, Chad M.

SUMMARY Aging is accompanied by profound changes in bladder function, leading to increased urinary frequency and incontinence that impair quality of life in humans and are recapitulated in mouse models. Bladder filling and emptying rely on precise mechanosensory feedback, yet how aging alters this sensory control remains unclear. PIEZO ion channels convert mechanical forces into cellular signals essential for bladder fullness sensation. Using inducible smooth-muscle specific Piezo1 deletion, we find that loss of Piezo1 attenuates aging-related bladder dysfunction. Dietary enrichment with margaric acid, a membrane-active fatty acid previously shown to inhibit PIEZO channels, reduced urinary dysfunction in aged mice. In humans, genotype–phenotype analyses reveal an association between a PIEZO1 gain-of-function variant and early-onset neuromuscular bladder dysfunction. Together, these findings define a smooth-muscle, PIEZO1-mediated mechanosensory basis for aging-related bladder dysfunction and introduce a non-invasive strategy for targeting PIEZO channels in vivo .

The urethra is considered a passive conduit for urine. Here, we reveal a surprising multicellular signaling pathway guiding the urethra’s dynamic response to an invading pathogen. Using a genetic approach in female mice, we deposited uropathogenic Escherichia coli into the distal urethra to establish a model of ascending urinary tract infection that progresses to the bladder within 4 h. We show that urethral neuroendocrine cells (UNECs), and the serotonin they synthesize, protect the bladder from bacterial colonization. We tested the hypothesis that serotonin initiates urethral contraction to expel ascending bacteria. We identified transient receptor potential cation channel subfamily A member 1, a noncanonical lipopolysaccharide receptor, in human and mouse UNECs and localized the serotonin receptors (HTR) 2B and 3, as well as the calcium-activated chloride channel anoctamin 1 (ANO1) to the pacemaker cells of the human and mouse urethra, the interstitial cells of Cajal (ICCs). HTR2B or ANO1 activation is sufficient for urethral contraction and is required for serotonin-induced mouse urethral contraction. Our results support the hypothesis that the urethra actively surveils its environment and responds to an ascending pathogen by evoking UNECs and ICC to induce urethral contraction and pathogen expulsion.

NBCe1 is an electrogenic Na + bicarbonate cotransporter expressed as three isoforms. NBCe1A is mainly found in the kidney (100% activity), NBCe1B is a general isoform (~25% activity), and NBCe1C is found in the nervous system (20% activity). This project was to characterize mice with loss of NBCe1 in the kidney and urogenital tract and to test isoform activity ± IRBIT. Previous work has shown that NBCe1‐B is activated when IRBIT is present and interacts with the N‐terminus (Nt). Even though NBCe1C shares this Nt, the effects of IRBIT on human NBCe1C are unknown. Interstitial Cells of Cajal (ICC)pacemaker cells in the gastrointestinal tract ( c‐kit + ) have NBCe1C, IRBIT and require bicarbonate for normal gut activity. Developmentally similar ICC cells are found in the urogenital tract; however, NBCe1C locations within the kidney and urogenital tract are unknown. Using c‐kit ‐copGFP and NBCe1A‐knockout mice, kidneys, ureters, prostate, bladder, and urethra were dissected and analyzed via direct imaging, sectioning, and immunofluorescence. Oocytes injected with NBCe1C ± IRBIT were voltage clamped to determine the cotransporter's activity. “Strings” of c‐kit + ‐cells were found in the copGFP & nbce1A kidneys. In nbce1 (+/−) ‐(Het) mice (Figure), prostate ducts appeared enlarged, and in nbce1A − / − kidney, c‐kit protein was broadly expressed, showing cluster colocalization with NBCe1C. NBCe1C is not obviously expressed in WT or copGFP mice. Electrophysiology data showed that IRBIT activates NBCe1C by ~10‐fold. As c‐kit is also a marker of stem cells, NBCe1C/c‐kit association and c‐kit increase in nbce1A − / − mice, could suggest that NBCe1A loss elicits kidney repair itself (proliferation) and causes expression of other NBCe1‐isoforms. Support or Funding Information R25‐DK101405, R01‐DK057061, U54‐DK100227 (Mayo) and U54‐DK104310 (UW‐Madison) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

BackgroundProstate stiffness and increased collagen content both associate with the presence of urinary symptoms in men but mechanisms responsible, including impact of age and androgens, are unknown. Dogs develop prostate‐related urinary dysfunction similar to humans, but mechanisms are also unknown. Mice have been used to examine how prostatic collagen accumulation affects voiding but whether mouse prostatic collagen organization resembles human or dog has not been evaluated. Here, we have constructed the first comprehensive, comparative maps of collagen architecture in canine, human, and mouse prostate and test whether canine prostatic collagen content is increased by aging and reduced by castration.MethodsComplete transverse prostate sections were stained with picrosirius red and imaged with confocal microscopy to reveal and compare collagen architecture across species. Canine prostatic collagen fiber length, diameter, and density in prostatic urethral, periurethral, peripheral, and capsular regions were quantified and compared among four experimental groups: young intact, young neutered, old intact, and old neutered dogs.ResultsSurprisingly, the majority of collagen was localized to the prostatic urethra in canine, human, and mouse. In canine and human, capsular regions also featured a dense collagen network but it appeared less dense than around prostatic urethra. Older, intact male canines exhibited overall denser prostate collagen fibers and had thicker capsular fibers than young, intact males. Prostatic glandular regions undergo dramatic atrophy and regression following castration, and our finding of neutered animals having increased collagen fiber density in both periurethral and peripheral regions is consistent with glandular contraction and increased proportion of stroma.ConclusionsCollagen architecture in dog appears similar to that in humans when cross sections are compared side‐by‐side. Canine collagen organization is affected by both age and androgen status, suggesting these factors may contribute to collagen accumulation in some males.