Collagen 17A1 in the Urothelium Regulates Epithelial Cell Integrity and Local Immunologic Responses in Obstructive Uropathy

Abstract

Collagen 17A1 (COL17A1), an epidermal hemidesmosome component, is ectopically induced in the urothelium of mouse and human renal pelvis (RP) in parallel with urinary tract–associated lymphoid structure development. Here, COL17A1 was induced in obstructive uropathy–prone ureter of humans and cats. To ascertain its function, murine urinary organs with unilateral ureteral obstruction (UUO) were analyzed during 1 week after surgery. One day after UUO, COL17A1 expression increased in urothelial cells of RP and ureter, and was positively correlated with renal tubulointerstitial lesions. A portion of RP where the smooth muscle layer from the ureter was interrupted was sensitive to urothelium deciduation and COL17A1 induction, showing urine leaked from the RP lumen into the parenchyma. After urine stimulation, cultured immune cells expressed Cxcl2, also up-regulated in CD11b⁺ cells following COL17A1 stimulation. One day after UUO, CXCL2⁺ CD11b⁺ cells infiltrated the urothelium-disrupted area. However, these numbers were significantly lower in Col17a1-deficient mice. COL17A1⁺ urothelial cells partially co-expressed cytokeratin-14, a progenitor cell marker for urothelium, whereas Col17a1-deficient mice had lower numbers of cytokeratin-14⁺ cells. Gene Ontology analysis revealed that expression of epithelial- and immune-associated genes was up-regulated and down-regulated, respectively, in the ureter of Col17a1-deficient mice 4 days after UUO. Thus, COL17A1 maintains urothelium integrity by regulating urothelial cell adhesion, proliferation, and differentiation, and activates local immune responses during obstructive uropathy in mammals.