Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies

迄今为止，估计约有3000万美国人患有慢性肾脏疾病，这是一种主要的慢性肾脏疾病。 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， 肾小球中的细胞，其主要功能是维持肾过滤屏障。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肾炎亚型 肾小球硬化（FSGS），特别是塌陷和细胞变异，以初始足细胞损伤为标志 和脱落，这会引发邻近壁上皮细胞（PEC）的异常增殖，导致 新月体或假新月体形成和最终的肾小球硬化。先前的研究表明， 足细胞和壁上皮细胞（佩奇）之间的相互作用可能在这些疾病的发病机制中起作用。 增生性病变，但机制尚不清楚。信号转导和激活剂的激活 转录因子3（STAT 3）参与了RPGN和塌陷的发生和发展。 FSGS。尽管STAT 3信号的激活在RPGN的发病机制中起重要作用， FSGS的亚型，STAT 3信号转导的调节仍有待探索。最近的研究表明， 锌指转录因子Krüppel样因子4（KLF 4）可能是一个关键的负调节因子， STAT 3信号传导。尽管KLF家族的几个成员与细胞分化有关， KLF 4首先被鉴定为增殖的关键负调节因子。我们的初步数据表明， 小鼠中足细胞特异性Klf 4缺失导致调节失调的肾小球STAT 3信号传导的激活， 足细胞损伤、PEC增殖和最终的FSGS和肾衰竭。此外，我们还表明， STAT 3信号的激活与肾活检组织肾小球中KLF 4的表达呈负相关， RPGN与对照标本相比。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和防止异常PEC增殖所必需的。 增生性肾小球病我们建议通过以下具体目标来检验这一假设：（1） 研究足细胞特异性KLF 4-STAT 3信号在增生性肾小球疾病中的必要作用， (2)确定增殖性肾小球病中介导足细胞-PEC串扰的中枢机制。 这项研究提案旨在通过阐明以下机制来解决该领域目前的空白： 在增殖性肾小球病中，足细胞损失触发佩奇的异常增殖。远景目标 我们项目的一个目的是确定诱导PEC增殖的失调途径， 在增殖性肾小球病的发展和/或进展中的靶点。

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.