title: Claudin-4 deficiency results in urothelial hyperplasia and lethal hydronephrosis.
abstract: Claudin (Cld)-4 is one of the dominant Clds expressed in the kidney and urinary tract, including selective segments of renal nephrons and the entire urothelium from the pelvis to the bladder. We generated Cldn4(-/-) mice and found that these mice had increased mortality due to hydronephrosis of relatively late onset. While the renal nephrons of Cldn4(-/-) mice showed a concomitant diminution of Cld8 expression at tight junction (TJ), accumulation of Cld3 at TJ was markedly enhanced in compensation and the overall TJ structure was unaffected. Nonetheless, Cldn4(-/-) mice showed slightly yet significantly increased fractional excretion of Ca(2+) and Cl(-), suggesting a role of Cld4 in the specific reabsorption of these ions via a paracellular route. Although the urine volume tended to be increased concordantly, Cldn4(-/-) mice were capable of concentrating urine normally on dehydration, with no evidence of diabetes insipidus. In the urothelium, the formation of TJs and uroplaques as well as the gross barrier function were also unaffected. However, intravenous pyelography analysis indicated retarded urine flow prior to hydronephrosis. Histological examination revealed diffuse hyperplasia and a thickening of pelvic and ureteral urothelial layers with markedly increased BrdU uptake in vivo. These results suggest that progressive hydronephrosis in Cldn4(-/-) mice arises from urinary tract obstruction due to urothelial hyperplasia, and that Cld4 plays an important role in maintaining the homeostatic integrity of normal urothelium.
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Fujita
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hamazaki
authors.forename: Yumi
authors.initials: Y
authors.lastname: Noda
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Minato
mesh_terms: D000818:Animals; D062506:Claudin-4 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006869:Hydronephrosis / Q000235:genetics / Q000378:metabolism*; D006965:Hyperplasia / Q000378:metabolism* / Q000473:pathology; D015151:Immunoblotting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019459:Urothelium / Q000378:metabolism* / Q000473:pathology
chemical_list: D062506:Claudin-4; C568158:Cldn4 protein, mouse