Alterations in bladder function associated with urothelial defects in uroplakin II and IIIa knockout mice

Abstract

Aims The effects of deleting genes encoding uroplakins II (UPII) and III (UPIIIa) on mouse bladder physiology/ dysfunction were studied in male and female wild type and knockout (KO) mice. Methods UPII, UPIIIa, and WT mice were catheterized using previously described techniques. Continuous cystometry was conducted in conscious, freely moving animals. Bladder strips were harvested after animal sacrifice and pharmacological studies and EFS were conducted in an organ chamber. Histological studies were also carried on with H&E staining to identify differences among the three mouse types. Results These studies have revealed numerous alterations, some of which were apparently gender-specific. Nonvoiding contractions were common in both UPII and UPIIIa KO mice, although more severe in the former. In particular, the increased bladder capacity, micturition pressure and demonstrable nonvoiding contractions observed in the male UPII KO’s, were reminiscent of an obstruction-like syndrome accompanied by evidence of emerging bladder decompensation, as reflected by an increased residual volume. Pharmacological studies revealed a modest, gender-specific reduction in sensitivity of isolated detrusor strips from UPII KO female mice to carbachol-induced contractions. A similar reduction was observed in UPIIIa KO female mice. Histological investigation showed urothelial hyperplasia in both UPII KO and UPIIIa KO mice, although again, apparently more severe in the former. Conclusions These results confirm and extend previous work to indicate that urothelial defects due to uroplakin deficiency are associated with significant alterations in bladder function and further highlight the importance of the urothelium to bladder physiology/dysfunction.

Cell biology and physiology of the uroepithelium

“…Deficiencies in UP expression are also manifested in altered bladder function as measured using cystometry (1). This technique measures the changes in intraluminal pressure that occur as the bladder is filled with buffer solutions through a catheter implanted in the dome of the bladder.…”

Exercise improves bladder function in diabetic mice

“…Mice were catheterized using previously described techniques. 13 Mice were anesthetized by an intraperitoneal injection of ketamine (80 mg/kg) and xylazine (10 mg/kg) and the ventral abdominal wall and upper back shaved. A midline longitudinal incision was made 0.5 cm above the urethral meatus.…”

“…13 Mice were placed in metabolic cages and cystometry was performed for a period of 2--3 hr. A filled 10 ml syringe was placed on an infusion pump and an infusion rate of 1.5 ml/hr was used.…”

Role of renal urothelium in the development and progression of kidney disease

“…Urothelium is known to play a key role in membrane permeability, modulating surface area and mediating host response to infection [7–10]. The embryonic origin of the urothelium is regionally distinct, with proximal urethra and bladder arising from endoderm and ureter and renal pelvis from mesoderm.…”

“…Superficial umbrella cells elaborating a rigid apical plaque that plays a key role in modulating membrane permeability, integrity, homeostasis and host response to pathogens [7–10]. Apical plaques are principally composed of Upk protein particles arranged into 2D crystals (Figure 2) [12].…”