Uroplakins in urothelial biology, function, and disease

Abstract

Urothelium covers the inner surfaces of the renal pelvis, ureter, bladder and prostatic urethra. Although morphologically indistinguishable, the urothelia in these anatomic locations differ in their embryonic origin and lineages of cellular differentiation, as reflected in their different uroplakin content, expandability during micturition and susceptibility to chemical carcinogens. Previously thought to be an inert tissue forming a passive barrier between the urine and blood, urothelia have recently been shown to have a secretory activity that actively modifies the urine composition. Urothelial cells express a number of ion channels, receptors and ligands, enabling them to receive and send signals and communicate with adjoining cells and their broader environment. The urothelial surface bears specific receptors that not only allow uropathogenic E. coli to attach to and invade into the bladder mucosa, but also provide a route by which the bacteria ascend via the ureters to the kidney to cause pyelonephritis. Genetic ablation of one or more uroplakin genes in mice causes severe retrograde vesicoureteral reflux, hydronephrosis and renal failure, conditions that mirror certain human congenital diseases. Clearly, abnormalities of the lower urinary tract can impact on the upper tract, and vice versa, through the urothelial connection. In this review, we highlight recent advances in the field of urothelial biology by focusing on the uroplakins, a group of urothelium-specific and differentiation-dependent integral membrane proteins. We discuss these proteins’ biochemistry, structure, assembly, intracellular trafficking and their emerging roles in urothelial biology, function and pathological processes. We also call attention to important areas where greater investigative efforts are warranted.

Gold nanoparticles as physiological markers of urine internalization into urothelial cells in vivo

“…Since there are contradicting results regarding endocytosis in urothelial cells, 3,19,37,38 we used the AuNPs to follow internalization into superficial urothelial cells of normal and neoplastic urothelium.…”

“…4,18 Urothelial plaques also cover cytoplasmic fusiform vesicles (FVs), which are implicated in the transport and incorporation of the urothelial plaques into the apical plasma membrane. 3,4,19 Nevertheless, involvement of FVs in the endocytosis of urothelial plaques from the apical plasma membrane is controversially discussed. 3,4,19 If FVs are involved in the endocytosis from the luminal side of the bladder, they would inevitably capture some urine despite their flattened shape.…”

“…3,4,19 Nevertheless, involvement of FVs in the endocytosis of urothelial plaques from the apical plasma membrane is controversially discussed. 3,4,19 If FVs are involved in the endocytosis from the luminal side of the bladder, they would inevitably capture some urine despite their flattened shape. 20,21 Therefore, demonstrating whether FVs are involved or not in the internalization of urine constituents would enhance our understanding of the permeability barrier function of the urothelium.…”

Innate Immune Response to Urinary Tract Infections Involving Escherichia coli

“…When TLR4 and TLR5 are bound by ligand they are phosphorylated on the cytoplasmic domain. Activation of the TLRs initiates signaling of immune and inflammation responses [22][23][24][25][26]. TLR4 activation by LPS or P fimbriae binding results in secretion of IL-6 and IL-8.…”

Cell Biology of Ureter Development

“…Prevention of movement of water and solutes through the apical-most epithelial layer is mediated by plaques made of UPK protein heterodimers. 45,46 UPK expression occurs early in urinary tract development, being present in epithelia lining the urogenital sinus. 47,48 In mutant mice lacking either UPK3A or UPK2 proteins, plaques are disorganized and urothelia are leaky.…”