The role of podocyte cGMP signalling in glomerular crosstalk and states of volume overload

足细胞 cGMP 信号在肾小球串扰和容量超负荷状态中的作用

• 批准号: 519307830
• 负责人: Dr. Matthias Johannes Hackl
• 金额: --
• 依托单位: Nephrologisches Forschungslabor
• 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/519307830?language=en
• 关键词: role; podocyte; cGMP; signalling; glomerular

Podocytes are specialized cells of the kidney filter and possess a complex cytoskeletal architecture with delicate secondary foot processes. So far, our knowledge about cGMP signaling in podocytes is quite limited. The cGMP signaling cascades are mediated by two main pathways. Volume overload triggers the production of natriuretic peptides in the heart and leads to increased fluid excretion in the kidney, while endothelial shear stress triggers NO production and relaxation of vascular smooth muscle cells. Our preliminary data demonstrates that both pathways increase podocyte cGMP concentration and suggests that podocytes respond to NO produced in endothelial cells. We will utilize acute kidney slices, intravital multiphoton imaging and a genetically encoded cGMP sensor to visualize cGMP levels in podocytes and to characterize triggers of cGMP signaling in podocytes in vivo. Furthermore, we will study alterations of cGMP signaling in disease states and investigate the impact of pharmacological interventions on the cGMP signaling pathways. We will put a special emphasis on investigating the newly discovered NO mediated endothelial-to-podocyte crosstalk in health and disease conditions, including an eNOS knock-out mouse line, and use a model of volume overload, a strong stimulus of natriuretic peptide signaling, to elucidate the role of the two main cGMP generating signaling pathways.

足细胞是肾脏滤过器的特化细胞，具有复杂的细胞骨架结构和精细的次级足突。到目前为止，我们对足细胞中cGMP信号传导的了解非常有限。cGMP信号级联由两个主要途径介导。容量超负荷触发心脏中利钠肽的产生并导致肾脏中液体排泄增加，而内皮剪切应力触发NO产生和血管平滑肌细胞的松弛。我们的初步数据表明，这两种途径增加足细胞cGMP浓度，并表明足细胞响应于内皮细胞中产生的NO。我们将利用急性肾切片，活体多光子成像和基因编码的cGMP传感器来可视化足细胞中的cGMP水平，并表征体内足细胞中cGMP信号传导的触发因素。此外，我们将研究疾病状态下cGMP信号的改变，并研究药物干预对cGMP信号通路的影响。我们将特别强调调查新发现的NO介导的内皮细胞对足细胞的串扰在健康和疾病的条件下，包括eNOS敲除小鼠线，并使用容量超负荷模型，利钠肽信号的强刺激，阐明两个主要的cGMP产生信号通路的作用。