Inhibition of eryptosis - a new strategy in the treatment of renal anemia

抑制红细胞凋亡——治疗肾性贫血的新策略

• 批准号: 426724658
• 负责人: Dr. Rosi Bissinger, Ph.D.
• 金额: --
• 依托单位: Innere Medizin IV: Endokrinologie und Diabetologie, Angiologie, Nephrologie und Klinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/426724658?language=en
• 关键词: Inhibition; eryptosis; new; strategy; treatment

Chronic kidney disease (CKD) leads to renal anemia, thereby affecting patients´ quality of life. Although renal anemia is often treated by application of erythropoietin (EPO), anemia cannot be fully compensated despite administration of EPO. In addition, the application of EPO promotes thrombosis formation and tumor growth. According to preliminary data from the applicant, it has been shown that the anemia in patients with CKD is due to an increased eryptosis which leads to an accelerated clearance of the erythrocytes from the bloodstream. As eryptotic erythrocytes adhere to the vessel wall, the increased eryptosis contributes not only to the genesis of renal anemia but also favors vascular occlusion. The mechanisms leading to increased eryptosis in patients with end-stage renal disease (ESRD) as well as in patients with non-dialysis chronic kidney disease (CKD) have not been understood yet. A common mechanism that plays a role in both ESRD and CKD is complement activation, as complement is active in both types of renal failure. Other possible causes of eryptosis could be uremic toxins. Furthermore, dysproteinemia due to proteinuria may also play a role. To be able to specifically treat renal anemia by inhibiting eryptosis, it is absolutely necessary to know the causes of its development. According to further preliminary data of the applicant and other colleagues, substances have already been found which inhibit eryptosis in vitro. The present application therefore seeks to elucidate the mechanisms of eryptosis contributing to renal anemia. Furthermore, the substances already effective in vitro are to be tested for their ability to inhibit the eryptosis in CKD in vivo. For this purpose, plasma samples from patients with ESRD and CKD will be used. Finally, the substances should be tested in an experimental approach in mice with doxorubicin-induced nephropathy and 5/6th nephrectomy. Upon successful testing of one or more substances, the substances could be considered a therapeutic option for the treatment of renal anemia in humans.

慢性肾病（CKD）导致肾性贫血，从而影响患者的生活质量。虽然肾性贫血通常通过应用促红细胞生成素（EPO）治疗，但尽管给予EPO，贫血仍不能完全补偿。此外，EPO的应用促进血栓形成和肿瘤生长。根据申请人的初步数据，已表明CKD患者的贫血是由于红细胞增多导致红细胞从血流中加速清除。由于红细胞凋亡粘附在血管壁上，红细胞凋亡增加不仅导致肾性贫血的发生，而且有利于血管闭塞。导致终末期肾病（ESRD）患者以及非透析慢性肾病（CKD）患者红细胞下垂增加的机制尚未了解。在ESRD和CKD中起作用的一种常见机制是补体激活，因为补体在两种类型的肾衰竭中都是活跃的。其他可能的原因可能是尿毒症毒素。此外，由于蛋白尿引起的蛋白异常血症也可能起作用。为了能够通过抑制红细胞下垂来特异性治疗肾性贫血，了解其发展的原因是绝对必要的。根据申请人和其他同事的进一步初步数据，已经发现了在体外抑制红细胞下垂的物质。因此，本申请试图阐明导致肾性贫血的红细胞下垂的机制。此外，将测试体外已经有效的物质在体内抑制CKD中的细胞凋亡的能力。为此，将使用ESRD和CKD患者的血浆样本。最后，这些物质应在阿霉素诱导的肾病和5/6肾切除的小鼠中进行实验性检测。在成功测试一种或多种物质后，这些物质可以被认为是治疗人类肾性贫血的治疗选择。