Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart.
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.
['Sörensen-Zender|Inga|I|', 'Bhayana|Sagar|S|', 'Susnik|Nathan|N|', 'Rolli|Veronique|V|', 'Batkai|Sandor|S|', 'Baisantry|Arpita|A|', 'Bahram|Siamak|S|', 'Sen|Payel|P|', 'Teng|Beina|B|', 'Lindner|Robert|R|', 'Schiffer|Mario|M|', 'Thum|Thomas|T|', 'Melk|Anette|A|', 'Haller|Hermann|H|', 'Schmitt|Roland|R|']
D054392:Adipokines D000818:Animals D001011:Aorta D002352:Carrier Proteins D002454:Cell Differentiation D004848:Epithelium D005347:Fibroblasts D005355:Fibrosis D017353:Gene Deletion D006023:Glycoproteins D057809:HEK293 Cells D006801:Humans D007668:Kidney D007674:Kidney Diseases D007676:Kidney Failure, Chronic D008297:Male D051379:Mice D009206:Myocardium D010766:Phosphorylation D014176:Protein Biosynthesis D051381:Rats D011994:Recombinant Proteins D029589:Seminal Plasma Proteins D015398:Signal Transduction D016212:Transforming Growth Factor beta D014517:Ureteral Obstruction D000090203:Zn-Alpha-2-Glycoprotein
epithelial fibrosis fibroblast GF-β renal fibrosis renal tubular epithelial cells