Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies

家长资助摘要： 迄今为止，估计约有3000万美国人患有慢性肾病，这是一种主要的健康问题。 美国的医疗负担。足细胞是终末分化的有丝分裂后内脏上皮细胞， 主要功能是维持肾滤过屏障的肾小球。肾小球疾病，如 快速进展性肾小球肾炎（RPGN）和局灶节段性肾小球硬化症亚型 （FSGS），特别是塌陷和细胞变体，以初始足细胞损伤和脱离为标志， 触发邻近壁上皮细胞（PEC）的异常增殖，导致新月形或假新月形 最终形成肾小球硬化。以前的研究表明足细胞和 壁上皮细胞（佩奇）可能在这些增生性病变的发病机制中发挥作用，但 机制尚不清楚。信号转导子和转录激活子3（STAT 3）的激活已经被证实。 参与RPGN和塌陷FSGS的启动和进展。虽然STAT 3的激活 信号传导在RPGN和FSGS亚型的发病机制中起着重要作用，STAT 3的调节 信号仍有待探索。最近的研究表明，锌指转录因子，Krüppel- 像因子4（KLF 4）一样，可能是STAT 3信号传导的关键负调节因子。虽然有几个成员 KLF家族与细胞分化有关，KLF 4首先被鉴定为关键负调节因子 扩散。我们的初步数据表明，小鼠足细胞特异性Klf 4的丢失使得小鼠的足细胞特异性Klf 4的表达降低。 激活失调的肾小球STAT 3信号传导、足细胞损伤、PEC增殖和最终的FSGS 和肾衰竭此外，我们发现STAT 3信号的激活与KLF 4负相关， 与对照标本相比，RPGN肾活检组织肾小球中的表达。基于这些 数据，我们假设足细胞特异性KLF 4是维持足细胞完整性所必需的， 预防增殖性肾小球病中的异常PEC增殖。我们建议检验这一假设 通过以下具体目的：（1）研究足细胞特异性KLF 4-STAT 3信号通路的必要作用 在增生性肾小球疾病中的作用，以及（2）确定介导足细胞-PEC串扰的中枢机制 增生性肾小球病。这项研究提案旨在通过阐明以下内容来解决该领域目前的一个空白： 足细胞丢失触发佩奇异常增殖的机制， 肾小球病我们项目的长期目标是确定诱导PEC的失调途径 可能在增殖性肿瘤的发展和/或进展中充当“可用药”靶标的增殖。 肾小球病

Parent Grant Abstract: 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.