title: Alpha8 Integrin (Itga8) Signalling Attenuates Chronic Renal Interstitial Fibrosis by Reducing Fibroblast Activation, Not by Interfering with Regulation of Cell Turnover.
abstract: The α8 integrin (Itga8) chain contributes to the regulation of cell proliferation and apoptosis in renal glomerular cells. In unilateral ureteral obstruction Itga8 is de novo expressed in the tubulointerstitium and a deficiency of Itga8 results in more severe renal fibrosis after unilateral ureteral obstruction. We hypothesized that the increased tubulointerstitial damage after unilateral ureteral obstruction observed in mice deficient for Itga8 is associated with altered tubulointerstitial cell turnover and apoptotic mechanisms resulting from the lack of Itga8 in cells of the tubulointerstitium. Induction of unilateral ureteral obstruction was achieved by ligation of the right ureter in mice lacking Itga8. Unilateral ureteral obstruction increased proliferation and apoptosis rates of tubuloepithelial and interstitial cells, however, no differences were observed in the tubulointerstitium of mice lacking Itga8 and wild type controls regarding fibroblast or proliferating cell numbers as well as markers of endoplasmic reticulum stress and apoptosis after unilateral ureteral obstruction. In contrast, unilateral ureteral obstruction in mice lacking Itga8 led to more pronounced tubulointerstitial cell activation i.e. to the appearance of more phospho-SMAD2/3-positive cells and more α-smooth muscle actin-positive cells in the tubulointerstitium. Furthermore, a more severe macrophage and T-cell infiltration was observed in these animals compared to controls. Thus, Itga8 seems to attenuate tubulointerstitial fibrosis in unilateral ureteral obstruction not via regulation of cell turnover, but via regulation of TGF-β signalling, fibroblast activation and/or immune cell infiltration.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Marek
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Lichtneger
authors.affiliation: Department of Nephrology and Hypertension, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Nada
authors.initials: N
authors.lastname: Cordasic
authors.affiliation: Department of Nephrology and Hypertension, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Karl F
authors.initials: KF
authors.lastname: Hilgers
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Volkert
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Fahlbusch
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rascher
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartner
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany.
authors.forename: Carlos
authors.initials: C
authors.lastname: Menendez-Castro
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis / Q000473:pathology; D005786:Gene Expression Regulation; D006720:Homozygote; D007249:Inflammation; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D039001:Integrin alpha Chains / Q000235:genetics* / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin
chemical_list: C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D039001:Integrin alpha Chains; D012097:Repressor Proteins; D000077022:Survivin; C093856:integrin alpha8