title: CD44v3-v10 reduces the profibrotic effects of TGF-β1 and attenuates tubular injury in the early stage of chronic obstructive nephropathy.
abstract: CD44 family members are cell surface glycoproteins, which are expressed on tubular epithelial cells (TEC) solely upon kidney injury and are involved in renal fibrosis development. Renal interstitial fibrosis is the final manifestation of chronic kidney diseases and is regulated by a complex network of cytokines, including the profibrotic factor transforming growth factor-β1 (TGF-β1) and the two antifibrotic cytokines bone morphogenic protein-7 (BMP-7) and hepatocyte growth factor (HGF). The present study investigates the potential role of CD44 standard (CD44s) and CD44v3-v10 (CD44v3) isoforms as modulators of the balance between TGF-β1 and HGF/BMP-7. CD44s is the shortest and most common isoform. CD44v3-v10 (CD44v3) has heparan sulfate moieties, which enable the binding to HGF/BMP-7, and hence, might exert renoprotective effects. Using transgenic mice overexpressing either CD44s or CD44v3 specifically on proximal TEC, we found that in vitro the overexpression of CD44v3 on primary TEC renders cells less susceptible to TGF-β1 profibrotic actions and more sensitive to BMP-7 and HGF compared with TEC overexpressing CD44s. One day after unilateral ureteric obstruction, obstructed kidneys from CD44v3 transgenic mice showed less tubular damage and myofibroblasts accumulation, which was associated with decreased TGF-β1 signaling and increased BMP-7 synthesis and signaling compared with kidneys from wild-type and CD44s transgenic mice. These data suggest that CD44v3 plays a renoprotective role in early stage of chronic obstructive nephropathy.
authors.affiliation: Dept. of Pathology, Rm. L2-112, Academic Medical Center, P.O. Box 22660, 1100 AZ, Amsterdam, The Netherlands. E.Rampanelli@amc.uva.nl.
authors.forename: Elena
authors.initials: E
authors.lastname: Rampanelli
authors.forename: Kasper
authors.initials: K
authors.lastname: Rouschop
authors.forename: Gwendoline J D
authors.initials: GJ
authors.lastname: Teske
authors.forename: Nike
authors.initials: N
authors.lastname: Claessen
authors.forename: Jaklien C
authors.initials: JC
authors.lastname: Leemans
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D005355:Fibrosis; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; C066855:HGF protein, human; C553307:HGF protein, mouse; D018960:Hyaluronan Receptors; D018836:Inflammation Mediators; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C525820:bmp7 protein, mouse; D017228:Hepatocyte Growth Factor
keywords: CD44; TGF-β1; UUO; fibrosis; tubules