Properties of the Urothelium that Establish the Blood–Urine Barrier and Their Implications for Drug Delivery

Abstract

The primary function of the urinary bladder is to store and periodically release urine. How the urothelium prevents permeation of water, ions, solutes, and noxious agents back into the bloodstream and underlying tissues as well as serving as a sensor and transducer of physiological and nociceptive stimuli is still not completely understood, and thus its unique functional complexity remains to be fully elucidated. This article reviews the permeation routes across urothelium as demonstrated in extensive morphological and electrophysiological studies on in vivo and in vitro urothelia. We consider the molecular and morphological structures of urothelium and how they contribute to the impermeability of the blood-urine barrier. Based on the available data, the extremely low permeability properties of urothelium can be postulated. This remarkable impermeability is necessary for the normal functioning of all mammals, but at the same time represents limitations regarding the uptake of drugs. Therefore, the current progress to overcome this most resilient barrier in our body for drug therapy purposes is also summarized in this review.

Highly Selective Anti-Cancer Activity of Cholesterol-Interacting Agents Methyl-β-Cyclodextrin and Ostreolysin A/Pleurotolysin B Protein Complex on Urothelial Cancer Cells

“…Thus, two human urothelial cell lines with different levels of cancer transformation, as T24 and RT4 cells, were analyzed for cytotoxicity along with NPU cells in the present study. Since normal human urothelium is difficult-to-obtain tissue, we used normal porcine urothelial cell culture, which shows identical differentiation markers as well as cell biological and histological similarities to human urothelium [ 35 , 50 ].…”

Proposing Urothelial and Muscle In Vitro Cell Models as a Novel Approach for Assessment of Long-Term Toxicity of Nanoparticles

“…The differences in susceptibility to NPs exposure between both cell models can be explained with the specific properties of each model. L6 cells grow in a monolayer, while NPU cells grow in several layers, and when differentiated, they form a tight barrier, which is impermeable to most substances [ 64 , 65 ]. Moreover, both NPU cell models have been shown to have an extremely low endocytic rate [ 65 ], which can result in a lack of NP internalization [ 66 ], as observed by TEM ( Figure 5 ).…”

“…L6 cells grow in a monolayer, while NPU cells grow in several layers, and when differentiated, they form a tight barrier, which is impermeable to most substances [ 64 , 65 ]. Moreover, both NPU cell models have been shown to have an extremely low endocytic rate [ 65 ], which can result in a lack of NP internalization [ 66 ], as observed by TEM ( Figure 5 ). Thus, the barrier function of NPU cells and low level of endocytosis is probably the main reason for large differences in viability compared to L6 cells.…”

Experimentally Induced Bladder Permeability Evokes Bladder Afferent Hypersensitivity in the Absence of Inflammation

“…At greater bladder pressures, these afferent signals progress to the cerebellum, providing sensation and conscious control of bladder voiding (Fowler et al, 2008;de Groat and Yoshimura, 2009). Whilst the urothelium has been shown to exhibit sensory functions (Birder and Andersson, 2013), the primary role of the urothelium is to provide a blood/urine barrier between the potentially toxic levels of urea, ammonia, and other noxious metabolites found within the urine and the underlying interstitium of the bladder (Lasič et al, 2015).…”