title: Tubulointerstitial de novo expression of the α8 integrin chain in a rodent model of renal fibrosis--a potential target for anti-fibrotic therapy?
abstract: In the normal kidney, the α8 integrin chain is expressed only on mesangial cells and vascular smooth muscle cells. α8 integrin ligates several matrix molecules including fibronectin, osteopontin and fibrillin-1. Recently, we detected de novo expression of α8 integrin on epithelial cells in renal cysts. We hypothesized that the α8 integrin chain is induced in tubular epithelia undergoing dedifferentiation and contributes to the fibrotic response in the tubulointerstitium (TI) after unilateral ureteral obstruction (UUO). After induction of UUO in rats by ligation of the right ureter, increased expression of the α8 integrin chain and its ligands was observed. In the TI, α8 integrin was localized to cytokeratin-positive epithelial cells and to interstitial fibroblasts; and colocalized with its ligands. In mice underexpressing α8 integrin UUO led to collagen deposition and fibroblast activation comparable to wild types. Mice lacking α8 integrin showed even more TI damage, fibroblast activation and collagen deposition after UUO compared to wild type mice. We conclude that the expression of the α8 integrin chain and its ligands is strongly induced in the TI after UUO, but underexpression of α8 integrin does not attenuate TI fibrosis. Mice lacking the α8 integrin chain are even more susceptible to TI damage than wild type mice. Thus, interactions of α8 integrin with its ligands do not seem to contribute to the development or progression of TI fibrosis in UUO. Targeting α8 integrin might not be a useful approach for anti-fibrotic therapy.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany. andrea.hartner@uk-erlangen.de
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartner
authors.forename: Carlos
authors.initials: C
authors.lastname: Menendez-Castro
authors.forename: Nada
authors.initials: N
authors.lastname: Cordasic
authors.forename: Ines
authors.initials: I
authors.lastname: Marek
authors.forename: Gudrun
authors.initials: G
authors.lastname: Volkert
authors.forename: Bernd
authors.initials: B
authors.lastname: Klanke
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rascher
authors.forename: Karl F
authors.initials: KF
authors.lastname: Hilgers
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D000071838:Fibrillin-1; D000071837:Fibrillins; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D039001:Integrin alpha Chains / Q000378:metabolism*; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D058990:Molecular Targeted Therapy; D053495:Osteopontin / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology; D054392:Adipokines
chemical_list: D000199:Actins; D024042:Collagen Type I; D016207:Cytokines; D000071838:Fibrillin-1; D000071837:Fibrillins; D005353:Fibronectins; D039001:Integrin alpha Chains; D008840:Microfilament Proteins; D053495:Osteopontin; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C000605725:Fbn1 protein, rat; C506897:Spp1 protein, rat; C093856:integrin alpha8