Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies

增殖性肾小球病中足细胞-壁上皮细胞串扰的介导机制

• 批准号: 10625384
• 负责人: John Cijiang He
• 金额: $ 50.89万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625384
• 关键词: Actins; Address; American; Attenuated; Binding; Cell Adhesion; Cell Cycle; Cell Cycle Checkpoint; Cell Differentiation process; Cellular Stress; ChIP-seq; Chronic Kidney Failure; Cytoskeleton; Data; Development; Differentiation Antigens; Disease; Epithelial Cell Proliferation; Epithelial Cells; Failure; Family; Feedback; Filtration; Focal and Segmental Glomerulosclerosis; Functional disorder; GKLF protein; Genes; Goals; Healthcare; Human; Hyperplasia; Injury; Injury to Kidney; Kidney; Kidney Failure; Kidney Glomerulus; Kruppel-like transcription factors; Laboratories; Lesion; Ligands; Maintenance; Mediating; Mediator; Mitotic; Modeling; Mouse Strains; Mus; Mutate; Organoids; Paracrine Communication; Parietal; Pathogenesis; Pathway interactions; Play; Predisposition; Prevention; Proliferating; Proteomics; Rapidly Progressive Glomerulonephritis; Receptor Activation; Regulation; Renal glomerular disease; Reporting; Research Proposals; Role; Signal Induction; Signal Transduction; Specimen; Stat3 protein; System; Testing; United States; Variant; Visceral; Zinc Fingers; care burden; cell type; comparison control; differential expression; druggable target; glomerulosclerosis; injured; innovation; kidney biopsy; knock-down; member; migration; mouse model; mutant; novel; paracrine; podocyte; postmitotic; prevent; receptor; single nucleus RNA-sequencing; therapeutic target; transcription factor; transcriptome sequencing

To date, approximately 30 million Americans are estimated to have chronic kidney disease, a major health care burden in the United States. Podocytes are terminally differentiated post-mitotic visceral epithelial cells in the glomerulus whose major function is the maintenance of the renal filtration barrier. Glomerular diseases such as Rapidly Progressive Glomerulonephritis (RPGN) and subtypes of Focal Segmental Glomerulosclerosis (FSGS), in particular collapsing and cellular variants, are marked by initial podocyte injury and detachment, which triggers aberrant proliferation of neighboring parietal epithelial cell (PEC), resulting in crescent or pseudocrescent formation and eventual glomerulosclerosis. Previous studies suggest the crosstalk between podocytes and parietal epithelial cells (PECs) might play a role in the pathogenesis of these hyperplastic lesions, but the mechanisms remain unclear. Activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been implicated in the initiation and progression of both RPGN and collapsing FSGS. Although activation of STAT3 signaling plays an important role in the pathogenesis of RPGN and subtypes of FSGS, the regulation of STAT3 signaling remains to be explored. Recent studies demonstrate that a zinc-finger transcription factor, Krüppel-Like Factor 4 (KLF4), might serve as a key negative regulator of STAT3 signaling. Although several members of the KLF family have been implicated in cell differentiation, KLF4 was first identified as a critical negative regulator of proliferation. Our preliminary data suggests that the podocyte-specific loss of Klf4 in mice renders the activation of dysregulated glomerular STAT3 signaling, podocyte injury, PEC proliferation, and eventual FSGS and renal failure. Furthermore, we showed that the activation of STAT3 signaling inversely correlated with KLF4 expression in the glomeruli of kidney biopsies with RPGN as compared to control specimens. Based on these data, we hypothesize that podocyte-specific KLF4 is required for the maintenance of podocyte integrity and prevention of aberrant PEC proliferation in proliferative glomerulopathies. We propose to test this hypothesis through the following specific aims: (1) Investigate the requisite role of podocyte-specific KLF4-STAT3 signaling in proliferative glomerulopathies and (2) Determine the central mechanisms mediating podocyte-PEC crosstalk in proliferative glomerulopathies. This research proposal aims to address a current gap in the field by elucidating the mechanisms by which podocyte loss triggers aberrant proliferation in the PECs in proliferative glomerulopathies. The long-term goal of our project is to identify dysregulated pathways inducing PEC proliferation that might serve as “druggable” targets in the development and/or progression of proliferative glomerulopathies.

迄今为止，据估计约有3000万美国人患有慢性肾脏疾病，这是一个主要 美国的医疗保健伯恩。足细胞是末端分化的有丝分化后内脏上皮 肾小球中主要功能的细胞是维持肾过滤屏障。肾小球 诸如快速进行性肾小球肾炎（RPGN）和局灶性分段的亚型等疾病 肾小球硬化（FSGS），特别是倒塌和细胞变异，以初始足细胞损伤为特征 和脱离，这会触发相邻顶层细胞（PEC）的异常增殖，从而导致 新月或伪后期形成和最终的肾小球硬化。先前的研究表明串扰 足细胞和顶叶上皮细胞（PEC）之间可能在这些发病机理中发挥作用 增生性病变，但机制尚不清楚。信号传感器的激活和激活因子 转录3（STAT3）已在RPGN和崩溃的主动性和进展中暗示 FSG。尽管Stat3信号的激活在RPGN和RPGN的发病机理中起重要作用 FSG的亚型，STAT3信号传导的调节仍有待探索。最近的研究表明 锌指转录因子，类似Krüppel样因子4（KLF4），可能是关键的负调节剂 STAT3信号。尽管KLF家族的几个成员在细胞分化中被暗示，但 KLF4首先被确定为增殖的关键负调节剂。我们的初步数据表明 小鼠中KLF4的足细胞特异性损失使肾小球STAT3信号失调的激活， 足细胞损伤，PEC增殖和最终的FSG和肾功能衰竭。此外，我们证明了 STAT3信号传导的激活与肾脏活检的肾小球的KLF4表达成反比 与对照样本相比，RPGN。基于这些数据，我们假设Podocyte特异性KLF4 维持足细胞完整性和预防异常PEC增殖所必需 增殖的肾小球病。我们建议通过以下特定目的检验这一假设：（1） 研究足细胞特异性KLF4-STAT3信号传导在增殖和肾小球病中的必要作用 （2）确定介导足细胞串扰的肾小球病中介导足细胞 - pec串扰的中心机制。 该研究建议旨在通过阐明该机制的机制来解决该领域的当前差距 足细胞损失会触发PEC中的异常增殖。长期目标 我们的项目是确定诱导PEC增殖的失调途径，可能是“可药” 肾小球病的发展和/或进展的目标。