title: Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart.
abstract: Zinc-α2-glycoprotein (AZGP1) is a secreted protein synthesized by epithelial cells and adipocytes that has roles in lipid metabolism, cell cycling, and cancer progression. Our previous findings in AKI indicated a new role for AZGP1 in the regulation of fibrosis, which is a unifying feature of CKD. Using two models of chronic kidney injury, we now show that mice with genetic AZGP1 deletion develop significantly more kidney fibrosis. This destructive phenotype was rescued by injection of recombinant AZGP1. Exposure of AZGP1-deficient mice to cardiac stress by thoracic aortic constriction revealed that antifibrotic effects were not restricted to the kidney but were cardioprotective. In vitro, recombinant AZGP1 inhibited kidney epithelial dedifferentiation and antagonized fibroblast activation by negatively regulating TGF-β signaling. Patient sera with high levels of AZGP1 similarly attenuated TGF-β signaling in fibroblasts. Taken together, these findings indicate a novel role for AZGP1 as a negative regulator of fibrosis progression, suggesting that recombinant AZGP1 may have translational effect for treating fibrotic disease.
authors: Departments of Nephrology and Hypertension.
authors: Inga
authors: I
authors: Sörensen-Zender
authors: Departments of Nephrology and Hypertension.
authors: Sagar
authors: S
authors: Bhayana
authors: Departments of Nephrology and Hypertension.
authors: Nathan
authors: N
authors: Susnik
authors: Immunogénétique Moléculaire Humaine, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; and.
authors: Veronique
authors: V
authors: Rolli
authors: Institute of Molecular and Translational Therapeutic Strategies, Integriertes Forschungs- und Behandlungszentrum Transplantation, Hannover Medical School, Hannover, Germany;
authors: Sandor
authors: S
authors: Batkai
authors: Departments of Nephrology and Hypertension, Pediatric Kidney, Liver, and Metabolic Diseases, and.
authors: Arpita
authors: A
authors: Baisantry
authors: Immunogénétique Moléculaire Humaine, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; and.
authors: Siamak
authors: S
authors: Bahram
authors: Departments of Nephrology and Hypertension.
authors: Payel
authors: P
authors: Sen
authors: Departments of Nephrology and Hypertension.
authors: Beina
authors: B
authors: Teng
authors: Cell Biology and.
authors: Robert
authors: R
authors: Lindner
authors: Departments of Nephrology and Hypertension.
authors: Mario
authors: M
authors: Schiffer
authors: Institute of Molecular and Translational Therapeutic Strategies, Integriertes Forschungs- und Behandlungszentrum Transplantation, Hannover Medical School, Hannover, Germany; National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors: Thomas
authors: T
authors: Thum
authors: Pediatric Kidney, Liver, and Metabolic Diseases, and.
authors: Anette
authors: A
authors: Melk
authors: Departments of Nephrology and Hypertension.
authors: Hermann
authors: H
authors: Haller
authors: Departments of Nephrology and Hypertension, schmitt.roland@mh-hannover.de.
authors: Roland
authors: R
authors: Schmitt
mesh_terms: D054392:Adipokines; D000818:Animals; D001011:Aorta / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D004848:Epithelium / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D017353:Gene Deletion; D006023:Glycoproteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D029589:Seminal Plasma Proteins / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000473:pathology; D000090203:Zn-Alpha-2-Glycoprotein
chemical_list: C488891:AZGP1 protein, human; D054392:Adipokines; D002352:Carrier Proteins; D006023:Glycoproteins; D011994:Recombinant Proteins; D029589:Seminal Plasma Proteins; D016212:Transforming Growth Factor beta; D000090203:Zn-Alpha-2-Glycoprotein
keywords: GF-β; epithelial; fibroblast; fibrosis; renal fibrosis; renal tubular epithelial cells