Lack of expression of miR-29a/b1 impairs bladder function in male mice.

Lower urinary tract symptoms (LUTS) refer to various urological diseases, and incomplete bladder emptying is common among affected patients. The etiology of LUTS is largely unknown, and investigations of LUTS suggest that bladder fibrosis contributes to pathogenesis of LUTS. MicroRNAs (miRNAs) are short (∼22 nucleotides), non-coding RNAs that repress target gene expression by a combination of mRNA degradation and translation inhibition.

Islet allografts expressing a PD-L1 and IDO fusion protein evade immune rejection and reverse preexisting diabetes in immunocompetent mice without systemic immunosuppression.

Allogeneic islet transplantation is a promising experimental therapy for poorly controlled diabetes. Despite pharmacological immunosuppression, long-term islet engraftment remains elusive. Here, we designed a synthetic fusion transgene coupling PD-L1 and indoleamine dioxygenase [hereafter PIDO] whose constitutive expression prevents immune destruction of genetically engineered islet allograft transplanted in immunocompetent mice.

A retrospective review of canine benign prostatic hyperplasia with and without prostatitis.

Benign prostatic hyperplasia (BPH) is the most common prostatic disorder in older intact male dogs, but despite its prevalence, there are inconsistencies in clinical diagnosis and treatment. Although prostate size was historically considered the hallmark feature of BPH in men, currently, there is only a weak correlation between prostate size and clinical severity. We performed a retrospective cohort study with the primary objective of assessing clinical signs, ultrasonographic findings, treatments, and outcomes in dogs diagnosed with BPH, with and without concurrent prostatitis.

Bisphenol-A analogs induce lower urinary tract dysfunction in male mice.

Bisphenol-A (BPA), an estrogenic endocrine disrupting chemical, significantly impacts numerous diseases and abnormalities in mammals. Estrogens are known to play an important role in the biology of the prostate; however, little is known about the role of bisphenols in the etiology of prostate pathologies, including benign prostate hyperplasia (BPH) and associated lower urinary tract dysfunction (LUTD). Bisphenol-F (BPF) and bisphenol-S (BPS) are analogs often used as substitutes for BPA; they are both reported to have in vitro and in vivo estrogenic effects similar to or more potent than BPA.

In utero and lactational PCB exposure drives anatomic changes in the juvenile mouse bladder.

Bladder dysfunction, including incontinence, difficulty emptying the bladder, or urgency to urinate is a pervasive health and quality of life concern. However, risk factors for developing these symptoms are not completely understood, and the influence of exposure to environmental chemicals, especially during development, on the formation and function of the bladder is understudied. Environmental contaminants such as polychlorinated biphenyls (PCBs) are known to pose a risk to the developing brain; however, their influence on the development of peripheral target organs, such as bladder, are unknown.

A mechanism linking perinatal 2,3,7,8 tetrachlorodibenzo-p-dioxin exposure to lower urinary tract dysfunction in adulthood.

Benign prostatic hyperplasia/lower urinary tract dysfunction (LUTD) affects nearly all men. Symptoms typically present in the fifth or sixth decade and progressively worsen over the remainder of life. Here, we identify a surprising origin of this disease that traces back to the intrauterine environment of the developing male, challenging paradigms about when this disease process begins.

The prostaglandin pathway is activated in patients who fail medical therapy for benign prostatic hyperplasia with lower urinary tract symptoms.

Background: Little is known about how benign prostatic hyperplasia (BPH) develops and why patients respond differently to medical therapy designed to reduce lower urinary tract symptoms (LUTS). The Medical Therapy of Prostatic Symptoms (MTOPS) trial randomized men with symptoms of BPH and followed response to medical therapy for up to 6 years. Treatment with a 5α-reductase inhibitor (5ARI) or an alpha-adrenergic receptor antagonist (α-blocker) reduced the risk of clinical progression, while men treated with combination therapy showed a 66% decrease in risk of progressive disease.

The influence of intermittent hypoxia, obesity, and diabetes on male genitourinary anatomy and voiding physiology.

We used male BTBR mice carrying the mutation, which are subject to severe and progressive obesity and diabetes beginning at 6 wk of age, to examine the influence of one specific manifestation of sleep apnea, intermittent hypoxia (IH), on male urinary voiding physiology and genitourinary anatomy. A custom device was used to deliver continuous normoxia (control) or IH to wild-type and (mutant) mice for 2 wk. IH was delivered during the 12-h inactive (light) period in the form of 90 s of 6% O followed by 90 s of room air.

Genetic background but not prostatic epithelial beta-catenin influences susceptibility of male mice to testosterone and estradiol-induced urinary dysfunction.

Urinary voiding dysfunction in aging men can cause bothersome symptoms and irreparable tissue damage. Underlying mechanisms are not fully known. We previously demonstrated that subcutaneous, slow-release testosterone and estradiol implants (T+E2) drive a pattern of urinary voiding dysfunction in male mice that resembles that of aging men.

A multi-omic investigation of male lower urinary tract symptoms: Potential role for JC virus.

Male lower urinary tract symptoms (LUTS) comprise a common syndrome of aging that negatively impacts quality of life. The etiology of LUTS is multifactorial, involving benign prostatic hyperplasia, smooth muscle and neurologic dysfunction, inflammation, sexually transmitted infections, fibrosis, and potentially dysbiosis, but this aspect remains poorly explored. We investigated whether the presence of infectious agents in urine might be associated with LUTS by combining next-generation DNA sequencing for virus discovery, microbiome analysis for characterization of bacterial communities, and mass spectrometry-based metabolomics.

A uropathogenic UTI89 model of prostatic inflammation and collagen accumulation for use in studying aberrant collagen production in the prostate.

Bacterial infection is one known etiology of prostatic inflammation. Prostatic inflammation is associated with prostatic collagen accumulation and both are linked to progressive lower urinary tract symptoms in men. We characterized a model of prostatic inflammation using transurethral instillations of UTI89 in C57BL/6J male mice with the goal of determining the optimal instillation conditions, understanding the impact of instillation conditions on urinary physiology, and identifying ideal prostatic lobes and collagen 1a1 prostatic cell types for further analysis.

An immunohistochemical prostate cell identification key indicates that aging shifts procollagen 1A1 production from myofibroblasts to fibroblasts in dogs prone to prostate-related urinary dysfunction.

Background: The identity and spatial distribution of prostatic cell types has been determined in humans but not in dogs, even though aging- and prostate-related voiding disorders are common in both species and mechanistic factors, such as prostatic collagen accumulation, appear to be shared between species. In this publication we characterize the regional distribution of prostatic cell types in the young intact dog to enable comparisons with human and mice and we examine how the cellular source of procollagen 1A1 changes with age in intact male dogs.

Methods: A multichotomous decision tree involving sequential immunohistochemical stains was validated for use in dog and used to identify specific prostatic cell types and determine their distribution in the capsule, peripheral, periurethral and urethral regions of the young intact canine prostate.

Micturition defects and altered bladder function in the mutant mouse model of aging.

Introduction And Objectives: Symptoms associated with detrusor underactivity (DU) or underactive bladder (UAB) can severely impact a person's quality of life, and growing old is the main etiological factor of DU and UAB. The gene has been associated with suppression of several aging phenotypes, and there is moderate expression in the bladder. Given this, we hypothesized that the klotho gene is involved in regulation of bladder function.

Best practices for cystometric evaluation of lower urinary tract function in muriform rodents.

Aims: Rodent cystometry has provided valuable insights into the impact of the disease, injury, and aging on the cellular and molecular pathways, neurologic processes, and biomechanics of lower urinary tract function. The purpose of this white paper is to highlight the benefits and shortcomings of different experimental methods and strategies and to provide guidance on the proper interpretation of results.

Methods: Literature search, selection of articles, and conclusions based on discussions among a panel of workers in the field.

Impact of sex, androgens, and prostate size on C57BL/6J mouse urinary physiology: urethral histology.

The National Institutes of Health leveled new focus on sex as a biological variable with the goal of understanding sex-specific differences in health and physiology. We previously published a functional assessment of the impact of sex, androgens, and prostate size on C57BL/6J mouse urinary physiology (Ruetten H, Wegner KA, Zhang HL, Wang P, Sandhu J, Sandhu S, Mueller B, Wang Z, Macoska J, Peterson RE, Bjorling DE, Ricke WA, Marker PC, Vezina CM. 317: F996-F1009, 2019).

Insight and Resources From a Study of the "Impact of Sex, Androgens, and Prostate Size on C57BL/6J Mouse Urinary Physiology.

The purpose of this symposium report is to summarize information from a session 3 oral presentation at the Society of Toxicologic Pathology Annual Symposium in Raleigh, North Carolina. Mice are genetically tractable and are likely to play an important role in elucidating environmental, genetic, and aging-related mechanisms of urinary dysfunction in men. We and others have made significant strides in developing quantitative methods for assessing mouse urinary function and our collaborators recently showed that aging male mice, like men, develop urinary dysfunction.

Impact of sex, androgens, and prostate size on C57BL/6J mouse urinary physiology: functional assessment.

Laboratory mice are used to identify causes of urinary dysfunction including prostate-related mechanisms of lower urinary tract symptoms. Effective use of mice for this purpose requires a clear understanding of molecular, cellular, anatomic, and endocrine contributions to voiding function. Whether the prostate influences baseline voiding function has not been specifically evaluated, in part because most methods that alter prostate mass also change circulating testosterone concentrations.

Void sorcerer: an open source, open access framework for mouse uroflowmetry.

Observational and experimental studies of rodent voiding behaviors have greatly contributed to our understanding of lower urinary tract function including the complex social, environmental, and internal stimuli that affect voiding in health and models of disease. Void spot assays (VSA), cystometry (awake or anesthetized), and uroflowmetry are techniques commonly used in rodent models to assess voiding. Uroflowmetry is non-invasive and can be performed multiple times in the same freely moving animals and can be used to generate synchronized video corresponding to each void to characterize micturition patterns (e.

Inhibition of the CXCL12/CXCR4 axis prevents periurethral collagen accumulation and lower urinary tract dysfunction in vivo.

Background: Several studies show that prostatic fibrosis is associated with male lower urinary tract dysfunction (LUTD). Development of fibrosis is typically attributed to signaling through the transforming growth factor β (TGF-β) pathway, but our laboratory has demonstrated that in vitro treatment of human prostatic fibroblasts with the C-X-C motif chemokine ligand 12 (CXCL12) chemokine stimulates myofibroblast phenoconversion and that CXCL12 has the capacity to activate profibrotic pathways in these cells in a TGF-β-independent manner. We have previously reported that feeding mice high-fat diet (HFD) results in obesity, type II diabetes, increased prostatic fibrosis, and urinary voiding dysfunction.

Void spot assay: recommendations on the use of a simple micturition assay for mice.

Investigators have for decades used mouse voiding patterns as end points for studying behavioral biology. It is only recently that mouse voiding patterns were adopted for study of lower urinary tract physiology. The spontaneous void spot assay (VSA), a popular micturition assessment tool, involves placing a mouse in an enclosure lined by filter paper and quantifying the resulting urine spot pattern.

Void spot assay procedural optimization and software for rapid and objective quantification of rodent voiding function, including overlapping urine spots.

Mouse urinary behavior is quantifiable and is used to pinpoint mechanisms of voiding dysfunction and evaluate potential human therapies. Approaches to evaluate mouse urinary function vary widely among laboratories, however, complicating cross-study comparisons. Here, we describe development and multi-institutional validation of a new tool for objective, consistent, and rapid analysis of mouse void spot assay (VSA) data.

Potential of Endocannabinoids to Control Bladder Pain.

Bladder-related pain is one of the most common forms of visceral pain, and visceral pain is among the most common complaints for which patients seek physician consultation. Despite extensive studies of visceral innervation and treatment of visceral pain, opioids remain a mainstay for management of bladder pain. Side effects associated with opioid therapy can profoundly diminish quality of life, and improved options for treatment of bladder pain remain a high priority.

Serotonin Receptor 5-HT3A Affects Development of Bladder Innervation and Urinary Bladder Function.

The autonomic and sensory nervous systems are required for proper function of all visceral organs, including the lower urinary tract (LUT). Despite the wide prevalence of bladder dysfunction, effective treatment options remain limited. Pelvic innervation regenerative strategies are promising, but surprisingly little is known about the molecular factors driving the development of bladder innervation.