Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart

Journal of the American Society of Nephrology : JASN
Inga Sörensen-ZenderRoland Schmitt

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.

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Citations

Mar 1, 2017·The Annals of Thoracic Surgery·Prashanth VallabhajosyulaEdward Cantu
Aug 17, 2017·Canadian Journal of Physiology and Pharmacology·Samir A E BashandyEnayat A Omara
Sep 19, 2019·American Journal of Physiology. Endocrinology and Metabolism·Dandan HuangFengxiao Zhang
Feb 2, 2017·Journal of the American Society of Nephrology : JASN·Eoin D O'SullivanDavid A Ferenbach
Dec 2, 2020·Nutrition, Metabolism, and Cardiovascular Diseases : NMCD·Leila SoltaniElgar Enamzadeh
Nov 27, 2020·Frontiers in Cardiovascular Medicine·Alexander E BerezinMichael Lichtenauer
Apr 13, 2021·Biochemical and Biophysical Research Communications·Kenji NishimuraKojiro Nagai
Jul 22, 2017·Kidney International·Roland Schmitt, Anette Melk

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