title: Tubular Dickkopf-3 promotes the development of renal atrophy and fibrosis.
abstract: Renal tubular atrophy and interstitial fibrosis are common hallmarks of etiologically different progressive chronic kidney diseases (CKD) that eventually result in organ failure. Even though these pathological manifestations constitute a major public health problem, diagnostic tests, as well as therapeutic options, are currently limited. Members of the dickkopf (DKK) family, DKK1 and -2, have been associated with inhibition of Wnt signaling and organ fibrosis. Here, we identify DKK3 as a stress-induced, tubular epithelia-derived, secreted glycoprotein that mediates kidney fibrosis. Genetic as well as antibody-mediated abrogation of DKK3 led to reduced tubular atrophy and decreased interstitial matrix accumulation in two mouse models of renal fibrosis. This was facilitated by an amplified, antifibrogenic, inflammatory T cell response and diminished canonical Wnt/β-catenin signaling in stressed tubular epithelial cells. Moreover, in humans, urinary DKK3 levels specifically correlated with the extent of tubular atrophy and interstitial fibrosis in different glomerular and tubulointerstitial diseases. In summary, our data suggest that DKK3 constitutes an immunosuppressive and a profibrotic epithelial protein that might serve as a potential therapeutic target and diagnostic marker in renal fibrosis.
authors.affiliation: Department of Cellular and Molecular Pathology and.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Federico
authors.affiliation: Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Meister
authors.affiliation: Department of Cellular and Molecular Pathology and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mathow
authors.affiliation: Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University Medical Center, Homburg, Germany.
authors.forename: Gunnar H
authors.initials: GH
authors.lastname: Heine
authors.affiliation: Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Moldenhauer
authors.affiliation: Department of Cellular and Molecular Pathology and.
authors.forename: Zoran V
authors.initials: ZV
authors.lastname: Popovic
authors.affiliation: Department of Cellular and Molecular Pathology and.
authors.forename: Viola
authors.initials: V
authors.lastname: Nordström
authors.affiliation: Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Kopp-Schneider
authors.affiliation: Department of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.affiliation: Clinical Biochemistry Group, Department of Internal Medicine and Policlinic IV, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nelson
authors.affiliation: Division of Pediatric Nephrology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.affiliation: Department of Cellular and Molecular Pathology and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Porubsky
authors.affiliation: Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University Medical Center, Homburg, Germany.
authors.forename: Danilo
authors.initials: D
authors.lastname: Fliser
authors.affiliation: Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.affiliation: Department of Cellular and Molecular Pathology and.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001284:Atrophy; D005355:Fibrosis; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology; D051436:Renal Insufficiency, Chronic / Q000378:metabolism / Q000473:pathology*; D060449:Wnt Signaling Pathway
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C405061:Dkk3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins