The lining of the urinary tract is a specialized tissue known as the urothelium. Its surface is covered by proteins called uroplakins, which are essential to the structure and function of the urinary bladder. These proteins assemble into distinct structures that fortify the urothelial cells, providing a protective barrier. This barrier separates underlying tissues from the potentially harmful substances in urine.
Understanding Uroplakin Proteins and Plaques
There are four primary types of uroplakin proteins: UPIa, UPIb, UPII, and UPIIIa. UPIa and UPIb are tetraspanins, meaning they cross the cell membrane four times, while UPII and UPIIIa are single-pass proteins that traverse the membrane only once. The synthesis of these proteins begins inside the cell’s endoplasmic reticulum.
For the proteins to function, they must pair up. UPIa forms a partnership with UPII, and UPIb pairs with UPIIIa, creating heterodimers. This pairing is required for the proteins to move from their point of synthesis for further assembly, as individual proteins would otherwise remain trapped.
These heterodimers form larger complexes called heterotetramers, and six of these assemble into a 16-nanometer particle. These particles are the building blocks of the structures on the bladder surface. They are arranged in a tightly packed, hexagonal pattern, creating two-dimensional crystals. These crystalline arrays are known as urothelial plaques, or asymmetric unit membranes (AUMs), and cover up to 90% of the surface of the outermost urothelial cells.
The Urothelial Barrier Function
The primary role of urothelial plaques is to create an impermeable barrier, preventing urine components like water, urea, and other solutes from leaking back into the body. The tight, crystalline arrangement of the uroplakin particles gives the membrane its strength and low permeability. This structure effectively contains the waste products stored in the bladder.
The bladder must also stretch to accommodate varying volumes of urine. The plaques themselves are rigid but are connected by flexible regions of the cell membrane known as “hinge” areas. As the bladder fills, these hinge regions unfold, allowing the urothelium’s surface area to expand without compromising the barrier’s integrity.
This structure ensures the protective lining remains intact even when the bladder is fully distended. The plaques provide the mechanical strength to prevent urothelial cells from rupturing under pressure. When the bladder empties, the membrane folds back along these hinge regions, decreasing the surface area.
Roles Outside the Urinary System
While best known for their function in the urinary tract, uroplakins have been detected in other body parts. Their presence in non-urothelial tissues suggests other biological roles. For instance, some uroplakin proteins are on the surface of mouse oocytes (egg cells), pointing to a potential involvement in fertilization.
Uroplakins on the egg’s surface may interact with sperm proteins, facilitating the binding that leads to fertilization. The absence of certain uroplakins can reduce in vitro fertilization rates in mice and may be associated with smaller litter sizes. Other non-urothelial tissues where uroplakins have been found include the stomach, prostate, and epididymis, though their functions there are not well understood.
Clinical Significance of Uroplakins
Alterations in uroplakin proteins are linked to several medical conditions. Uroplakins can act as attachment sites for pathogens, contributing to urinary tract infections (UTIs). For example, certain strains of uropathogenic E. coli, a common cause of UTIs, have proteins that bind to uroplakins. This allows the bacteria to adhere to the bladder wall and establish an infection. Defects in the uroplakin layer can also compromise the barrier, making an individual more susceptible to recurrent infections.
Uroplakins are also significant in urothelial cancer (bladder cancer). Because they are specific products of urothelial cells, they serve as molecular markers. The expression levels of different uroplakins can change during cancer development. Monitoring uroplakins or their fragments in urine or tissue can aid in the diagnosis and staging of urothelial carcinoma.
An improperly formed urothelial barrier might contribute to conditions like interstitial cystitis, or bladder pain syndrome. Increased permeability of the urothelium could allow urine substances to penetrate the bladder wall, causing inflammation and pain. The study of uroplakins offers potential targets for new diagnostic tools and therapies for various urological diseases.