The bladder undergoes large shape changes as it fills and empties and experiences complex mechanical forces. These forces become abnormal in diseases of the lower urinary tract such as overactive bladder, neurogenic bladder and urinary retention. As the primary mechanosensors linking the actin cytoskeleton to the extracellular matrix (ECM), integrins are likely to play vital roles in maintaining bladder smooth muscle (BSM) homeostasis. In a tamoxifen-inducible smooth muscle conditional knockout of β1-integrin there was concomitant loss of α1- and α3-integrins from BSM and upregulation of αV- and β3-integrins. Masson's staining showed a reduction in smooth muscle with an increase in collagenous ECM. Functionally mice exhibited a changing pattern of urination by voiding spot assay up to eight weeks after tamoxifen. By eight weeks there was increased frequency with reductions in voided volume, consistent with overactivity. Cystometrograms confirmed there was a significant reduction in intercontractile interval with reduced maximal bladder pressure. Muscle strip myography revealed a loss of contraction force in response to electrical field stimulation, that was entirely due to loss of muscarinic contractility. Quantitative western blotting showed a loss of M3 receptor and no change in P2X1. qPCR on extracellular matrix and interstitial genes revealed loss of Ntpd2, a marker of an interstitial cell subpopulation; and an upregulation of S100A4 which is often associated with fibroblasts. Collectively, the data show that loss of appropriate mechanosensation through integrins results in cellular and extracellular remodeling, and concomitant bladder dysfunction that resembles lower urinary tract symptoms seen in older people.

Lower urinary tract symptoms are extremely common in people with diabetes and obesity, but the causes are unclear. Furthermore, it has proven difficult to reliably demonstrate bladder dysfunction in diabetic mouse models, thus limiting the ability to gain mechanistic insights. Therefore, the main objective of this experimental study was to characterize diabetic bladder dysfunction in three promising polygenic mouse models of type 2 diabetes. We performed periodic assessments of glucose tolerance and micturition (void spot assay) for eight to twelve months. Males and females and high-fat diets were tested. NONcNZO10/LtJ mice did not develop bladder dysfunction over twelve months. TALLYHO/JngJ males were severely hyperglycemic from two months of age (fasted blood glucose ~550 mg/dL), while females were moderately so. Although males exhibited polyuria, neither they nor the females exhibited bladder dysfunction over nine months. KK.Cg-Ay/J males and females were extremely glucose intolerant. Males exhibited polyuria, a significant increase in voiding frequency at four months (compensation), followed by a rapid drop in voiding frequency by six months (decompensation) which was accompanied by a dramatic increase in urine leakage, indicating loss of outlet control. At eight months, male bladders were dilated. Females also developed polyuria but compensated with larger voids. We conclude KK.Cg-Ay/J male mice recapitulate key symptoms noted in patients and are the best model of the three to study diabetic bladder dysfunction.