Therapeutic strategies and molecular mediators of renal pathology in cardiorenal syndrome type 2

2型心肾综合征的治疗策略和肾脏病理的分子介质

• 批准号: 453080792
• 负责人: Dr. Thomas Daniel Krämer
• 金额: --
• 依托单位国家: 德国
• 项目类别: WBP Position
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/453080792?language=en
• 关键词: Therapeutic; strategies; molecular; mediators; renal

Cardiac and renal dysfunction frequently coexist and form a pathophysiological cycle with an adverse impact on short- and long-term morbidity and mortality. The clinical entity cardiorenal syndrome (CRS) describes the combined dysfunction of the heart and the kidney. CRS type 2 is characterized by chronic heart failure causing progressive chronic kidney disease (CKD) and recognized as the most frequent subtype of CRS. Worsening kidney function in the context of heart failure significantly increases adverse outcomes, but therapeutic options to slow progression of CKD and prevent end-stage renal disease are limited and in need for expansion. While the impact of hemodynamic parameters such as hypoperfusion and renal congestion are discussed as driving forces for the development of CKD in CRS type 2, little is known about the non-hemodynamic pathways relevant for the onset and progression of CKD in CRS type 2. This project aims to establish the role of extracellular vesicle (EV) dependent interorgan communication by microRNA (miRNA) transfer from cardiac to renal cells as a non-hemodynamic factor relevant for the renal pathology in CRS type 2 and to explore its therapeutic implications. The underlying hypothesis for this project is that cardiomyocytes under conditions of chronic heart failure secrete EVs containing miRNAs that target renal fibroblasts and pericytes which induce myofibroblast transdifferentiation and promote renal fibrogenesis. The following aims are set to address this hypothesis: (Aim 1) angiotensin II treated cardiomyocyte derived EVs as wells as serum derived EVs from mice suffering chronic heart failure are characterized and analyzed for the capacity of myofibroblast transdifferentiation of renal target cells (fibroblasts and pericytes) in vitro and in vivo. Cell culture derived fluorescently labeled EVs detected by in vivo imaging system (IVIS) and transgenic inducible green fluorescent protein (GFP) EV reporter mouse strains will be used to identify renal target cells in vivo. (Aim 2) The transverse aortic constriction (TAC) model mimicking CRS type 2 will be used to identify candidate EV miRNAs (small RNA sequencing) that precede or accompany pathologic changes in renal function, structure and composition in response to heart insufficiency. (Aim 3) In addition, preexisting compounds such as lycorine, that has been recently identified by Thomas Thums´ group, will be tested for its therapeutic potential in primary renal disease as well as CRS type 2 due to its antifibrotic capacity.

心脏和肾功能不全经常共存，形成一个病理生理循环，对短期和长期发病率和死亡率产生不利影响。心肾综合征（CRS）是一种心肾功能不全的综合性疾病。CRS 2型的特征是慢性心力衰竭导致进行性慢性肾病（CKD），被认为是CRS的最常见亚型。心力衰竭背景下肾功能恶化会显着增加不良结局，但减缓慢性肾病进展和预防终末期肾病的治疗选择有限，需要扩展。虽然血流动力学参数（如灌注不足和肾充血）的影响被讨论为CRS 2型中CKD发展的驱动力，但对CRS 2型中CKD发作和进展相关的非血流动力学途径知之甚少。本项目旨在通过microRNA（miRNA）从心脏细胞转移到肾脏细胞来确定细胞外囊泡（EV）依赖的器官间通讯作为与CRS 2型肾脏病理相关的非血流动力学因素的作用，并探索其治疗意义。该项目的基本假设是慢性心力衰竭条件下的心肌细胞分泌含有靶向肾成纤维细胞和周细胞的miRNA的EV，其诱导肌成纤维细胞转分化并促进肾纤维化。（目的1）表征血管紧张素II处理的心肌细胞衍生的EV以及来自患有慢性心力衰竭的小鼠的血清衍生的EV的威尔斯孔，并分析体外和体内肾靶细胞（成纤维细胞和周细胞）的肌成纤维细胞转分化的能力。通过体内成像系统（IVIS）检测的细胞培养衍生的荧光标记EV和转基因诱导型绿色荧光蛋白（GFP）EV报告基因小鼠品系将用于体内鉴定肾靶细胞。(Aim 2）模拟CRS 2型的横向主动脉缩窄（TAC）模型将用于鉴定响应于心功能不全的肾功能、结构和组成的病理变化之前或伴随的候选EV miRNA（小RNA测序）。(Aim 3）此外，托马斯图姆斯小组最近发现的先前存在的化合物，如石蒜碱，由于其抗纤维化能力，将测试其在原发性肾脏疾病以及CRS 2型中的治疗潜力。