Therapeutic potential of Zinc-alpha2-Glycoprotein (AZGP1) in chronic kidney and heart disease

锌-α2-糖蛋白(AZGP1)是一种41 kDa的分泌型蛋白，在多种组织中均有表达。AZGP1的多效性生物效应已被描述，但其生理功能尚未明确。循环中的AZGP1通过肾脏被清除，因此慢性肾脏疾病患者血清AZGP1水平升高。我们在siRNA敲除研究中观察到，AZGP1在调节肾脏修复反应中发挥着重要作用。在急性损伤的背景下，AZGP1的抑制导致肾小管脱分化增加和间质纤维化增加。这些发现表明该蛋白具有保护肾脏、抗纤维化的作用。对不同肾脏损伤模型中基因缺失的AZGP1-/-小鼠的分析证实了这些影响。为了阐明治疗前景，我们在初步研究中测试了AZGP1的外源性应用，发现重组AZGP1保护上皮完整性并抑制促纤维化过程。在体外，AZGP1拮抗转化生长因子-β依赖的肾上皮细胞和成纤维细胞的激活。在主动脉缩窄型心肌肥厚(TAC)模型中，我们也发现了类似的心脏保护机制。在本申请中，我们想要验证和扩展这些发现。为此，我们想要测试外源性AZGP1在肾脏(单侧输尿管梗阻、马兜铃酸肾病、缺血/再灌注、转基因转化生长因子-β过度表达)和心脏(TAC)的各种应激模型中的保护作用。同时，AZGP1条件过表达的转基因策略将被用于测试单个AZGP1水平的影响，并评估AZGP1活性的差异，这取决于合成AZGP1的组织。最后，在第一个翻译步骤中，将进行相关性分析，以确定AZGP1在肾病患者中的保护意义。为此，我们将在透析患者中进行一项前瞻性队列研究，以评估AZGP1对心血管死亡率和发病率的预测价值。此外，我们还将分析血清AZGP1与肾移植受者移植结果的相关性。总体而言，我们预计所要求的计划的结果不仅将提高我们对AZGP1作用的基本了解，还将使我们能够对这种蛋白质用于治疗目的的潜力做出现实的估计。

Zinc-alpha2-glycoprotein (AZGP1) is a 41 kDa secreted protein that is expressed in many different tissues. Pleiotropic bioeffects have been described for AZGP1, but the physiological function has not been conclusively clarified. Circulating AZGP1 is eliminated via the kidney so that increased serum AZGP1 serum levels occur in patients with chronic kidney disease. We have observed in siRNA knockdown studies that AZGP1 plays an important role in the regulation of the renal repair response. In the context of acute damage, kockdown of AZGP1 resulted in increased tubular dedifferentiation and increased interstitial fibrosis. These findings indicated a nephroprotective, anti-fibrotic effect of the protein. The analysis of genetically deleted AZGP1-/- mice in different renal damage models confirmed these effects. To elucidate therapeutic perspectives, we have tested the exogenous application of AZGP1 in preliminary studies and found that recombinant AZGP1 protects epithelial integrity and inhibits pro-fibrotic processes. In vitro, AZGP1 antagonized TGF-beta-dependent activation of renal epithelial cells and fibroblasts. We also found a similar mechanism of protection in the heart using the model of aorto-constrictive cardiac hypertrophy (TAC). In the present application we want to verify and expand these findings. For this purpose, we want to test the protective effect of exogenous AZGP1 in various stress models of the kidney (unilateral ureteral obstruction, aristolochic acid nephropathy, ischemia/reperfusion, transgenic TGF-beta over-expression) and the heart (TAC). In parallel, a transgenic strategy for the conditional over-expression of AZGP1 is to be used to test the effects of individual AZGP1 levels and to assess differences in AZGP1 activity depending on the tissue where it is synthesized. Finally, in a first translational step, correlation analyzes are to be carried out to determine the protective significance of AZGP1 in patients with kidney disease. For this purpose, we will perform a prospective cohort study in dialysis patients to evaluate the predictive value of AZGP1 for cardiovascular mortality and morbidity. Furthermore, we will analyze the correlation between serum AZGP1 and transplant outcome in kidney allograft recipients. Overall, we expect that the results of the requested program will not only improve our basic understanding of the role of AZGP1 but will also allow us to make a realistic estimation of the potential of this protein for therapeutic purposes.