Defining the interaction of platelets, neutrophil extracellular traps and thrombo-inflammation in diabetic kidney disease

定义糖尿病肾病中血小板、中性粒细胞胞外陷阱和血栓炎症之间的相互作用

• 批准号: 524693705
• 负责人: Professor Dr. Berend Isermann
• 金额: --
• 依托单位: Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/524693705?language=en
• 关键词: Defining; interaction; platelets; neutrophil; extracellular

Diabetic kidney disease (DKD) is a major cause of end-stage renal disease. This makes DKD a major cause of morbidity and mortality in diabetic patients and increases the burden on the healthcare system. Glomerular endothelial dysfunction and associated coagulation activation have been linked with glomerular filtrations barrier (GFB) disruption and DKD progression. While a homeostatic function of soluble coagulation regulators at the GFB independent of hemostasis has been described, mechanistic studies linking platelet activation, thrombo-inflammation and glomerular endothelial dysfunction are missing. Thrombo-inflammatory mechanisms are characterized by an interaction of platelets with innate immune cells, such as neutrophils. Additionally, DKD severity is associated with accumulation of immune cells in the kidney. Neutrophils can induce inflammation by formation of neutrophil extracellular traps. In our preliminary work we detected NETs in glomeruli of diabetic mice. Platelets exacerbate glucose-induced NET-formation on glomerular endothelial cells and in glomeruli in vivo, which is associated with increased NLRP3 inflammasome activation and impaired endothelial function (reduction of eNOS, KLF2, KLF4, TM). Additional data suggest that NET formation not only leads to histone citrullination, but also to citrullination of endothelial proteins. Based on these preliminary data, we hypothesize that platelets interact with neutrophils, promoting formation, accumulation, and stabilization of NETs which exacerbate renal sterile inflammation (NLRP3 inflammasome) and impairs endothelial function in DKD. In order to address this hypothesis, we propose the following aims: (1) Defining the regulation, mechanistic relevance, and translational importance of platelet associated NET-formation in DKD; (2) Establish the relevance of the NLRP3 inflammasome for platelet and NET mediated sterile inflammation in DKD; (3) Characterizing the mechanistic relevance of the endothelial Klf-2/4-thrombomodulin axis in platelet-NET-dependent endothelial dysfunction and renal thrombo-inflammation; (4) Characterizing the role of protein citrullination for endothelial dysfunction and renal thrombo-inflammation; these studies will provide new insights into the mechanisms of glomerular thrombo-inflammation in DKD and evaluate the relevance of platelet and/or NET inhibition to prevent or reduce glomerular endothelial dysfunction in DKD. These will thus provide insights into perpetuating inflammatory mechanisms at the GFB, which may be therapeutically targeted.

糖尿病肾病（DKD）是终末期肾脏疾病的主要原因。这使得DKD成为糖尿病患者发病和死亡的主要原因，并增加了医疗保健系统的负担。肾小球内皮功能障碍和相关凝血激活与肾小球滤过屏障（GFB）破坏和DKD进展有关。虽然已经描述了可溶性凝血调节剂在GFB中独立于止血的稳态功能，但缺乏将血小板激活、血栓炎症和肾小球内皮功能障碍联系起来的机制研究。血小板炎症机制的特点是血小板与先天免疫细胞（如中性粒细胞）的相互作用。此外，DKD的严重程度与肾脏中免疫细胞的积累有关。中性粒细胞可以通过形成中性粒细胞胞外陷阱诱导炎症。在我们的前期工作中，我们在糖尿病小鼠肾小球中检测到了NETs。血小板在体内加剧葡萄糖诱导的肾小球内皮细胞和肾小球内net的形成，这与NLRP3炎性体激活增加和内皮功能受损（eNOS、KLF2、KLF4、TM减少）有关。其他数据表明，NET的形成不仅导致组蛋白瓜氨酸化，还导致内皮蛋白瓜氨酸化。基于这些初步数据，我们假设血小板与中性粒细胞相互作用，促进NETs的形成、积累和稳定，从而加剧肾无菌炎症（NLRP3炎性体）并损害DKD的内皮功能。为了解决这一假设，我们提出以下目标：(1)定义DKD中血小板相关net形成的调控、机制相关性和翻译重要性；(2)建立NLRP3炎性小体与血小板和NET介导的DKD无菌性炎症的相关性；(3)表征内皮细胞klf -2/4-血栓调节蛋白轴在血小板- net依赖性内皮功能障碍和肾血栓炎症中的机制相关性；(4)蛋白瓜氨酸化在内皮功能障碍和肾血栓炎症中的作用；这些研究将为DKD患者肾小球血栓炎症的机制提供新的见解，并评估血小板和/或NET抑制与预防或减少DKD患者肾小球内皮功能障碍的相关性。因此，这些将提供对GFB持续炎症机制的见解，这可能是治疗目标。