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

锌-α2-糖蛋白（AZGP1）在慢性肾病和心脏病中的治疗潜力

基本信息

批准号：
361891910
负责人：
Professor Dr. Roland Schmitt
金额：
--
依托单位：
Klinik für Nieren- und Hochdruckerkrankungen
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/361891910?language=en
关键词：
Therapeutic potential Zinc alpha2 Glycoprotein

项目摘要

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.

锌-α 2-糖蛋白（AZGP 1）是一种41 kDa的分泌蛋白，在许多不同的组织中表达。已经描述了AZGP 1的多效性生物效应，但其生理功能尚未最终阐明。循环中的AZGP 1通过肾脏消除，因此慢性肾病患者的血清AZGP 1血清水平升高。我们在siRNA敲除研究中观察到，AZGP 1在肾修复反应的调节中起重要作用。在急性损伤的情况下，AZGP 1的kockdown导致肾小管去分化增加和间质纤维化增加。这些发现表明蛋白质具有肾保护、抗纤维化作用。在不同的肾损伤模型中对基因缺失的AZGP 1-/-小鼠的分析证实了这些作用。为了阐明治疗前景，我们在初步研究中测试了AZGP 1的外源性应用，发现重组AZGP 1保护上皮完整性并抑制促纤维化过程。在体外，AZGP 1拮抗肾上皮细胞和成纤维细胞的TGF-β依赖性活化。我们还发现了一个类似的机制，在心脏的保护使用模型的缩窄性心肌肥厚（TAC）。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AZGP 1在肾脏（单侧输尿管梗阻、马兜铃酸肾病、缺血/再灌注、转基因TGF-β过表达）和心脏（TAC）的各种应激模型中的保护作用。与此同时，AZGP 1条件性过表达的转基因策略将用于测试个体AZGP 1水平的影响，并评估AZGP 1活性的差异，这取决于其合成的组织。最后，在第一个翻译步骤中，进行相关性分析以确定AZGP 1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AZGP 1对心血管死亡率和发病率的预测价值。此外，我们将分析血清AZGP 1与肾移植受者移植结果的相关性。总的来说，我们希望所要求的项目的结果不仅能提高我们对AZGP 1作用的基本理解，而且还能让我们对这种蛋白质用于治疗目的的潜力做出现实的估计。