Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart
Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart
复制标题
DOI：
10.1681/asn.2014050485
复制
发表时间：
2015-11-01
影响因子：
13.6
通讯作者：
Schmitt, Roland
中科院分区：
文献类型：
--
作者：
Soerensen-Zender, Inga;Bhayana, Sagar;Schmitt, Roland
锌- α 2-糖蛋白（AZGP1）是一种由上皮细胞和脂肪细胞合成的分泌蛋白，在脂质代谢、细胞周期和癌症进展中起作用。我们之前在AKI中的发现表明AZGP1在纤维化调控中的新作用，这是CKD的一个统一特征。通过使用两种慢性肾损伤模型，我们发现AZGP1基因缺失的小鼠发生了更多的肾纤维化。通过注射重组AZGP1挽救了这种破坏性表型。将azgp1缺陷小鼠暴露于胸主动脉收缩引起的心脏应激中，发现抗纤维化作用不仅限于肾脏，而且具有心脏保护作用。在体外，重组AZG P1通过负调控tgf - β信号通路抑制肾上皮去分化并拮抗成纤维细胞活化。具有高水平AZGP1的患者血清类似地减弱了成纤维细胞中的tgf - β信号。综上所述，这些发现表明AZGP1作为纤维化进展的负调节因子的新作用，表明重组AZGP1可能具有治疗纤维化疾病的转化作用。
Zinc-alpha 2-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 AZG P1 inhibited kidney epithelial dedifferentiation and antagonized fibroblast activation by negatively regulating TGF-beta signaling. Patient sera with high levels of AZGP1 similarly attenuated TGF-beta 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.