Mechanisms mediating podocyte-parietal epithelial cell crosstalk in proliferative glomerulopathies

家长赠款摘要： 到目前为止，估计大约有3000万美国人患有慢性肾脏疾病，这是一种主要的健康问题 美国的护理负担。足细胞是有丝分裂后终末分化的内脏上皮细胞。 肾小球，其主要功能是维持肾滤过屏障。肾小球疾病，如 AS快速进展性肾小球肾炎(RPGN)与局灶节段性肾小球硬化亚型 (FSGS)，特别是塌陷和细胞变体，以最初的足细胞损伤和脱离为标志，这 触发邻近顶叶上皮细胞(PEC)的异常增殖，导致新月或假新月 形成和最终的肾小球硬化。之前的研究表明足细胞和足细胞之间的串扰 壁上皮细胞(PECs)可能在这些增生性病变的发病机制中发挥作用，但 机制仍不清楚。转录信号转导和激活因子3(STAT3)的激活 与RPGN和崩溃的FSGS的启动和发展有关。尽管STAT3的激活 信号转导在RPGN的发病机制、FSGS亚型、STAT3的调控中起重要作用 信号传递仍有待探索。最近的研究表明，锌指转录因子Krüppel- 与第4因子(KLF4)一样，可能是STAT3信号转导的关键负性调节因子。虽然有几个成员 KLF家族与细胞分化有关，KLF4首先被确定为一个关键的负调控因子 扩散的可能性。我们的初步数据表明，小鼠足细胞特异性KLF4的丢失使 肾小球STAT3信号的激活、足细胞损伤、PEC增殖和最终的FSGS 和肾衰竭。此外，我们还发现，STAT3信号的激活与KLF4呈负相关 与对照组相比，肾小球肾炎患者肾小球中的表达。基于这些 数据，我们假设足细胞特异性KLF4是维持足细胞完整性所必需的，并且 增生性肾小球疾病中PEC异常增殖的预防。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KLF4-STAT3信号的必要作用 在增生性肾小球疾病中的作用以及(2)确定介导足细胞-PEC串扰的中心机制 在增生性肾小球疾病中。这项研究提案旨在通过澄清以下内容来解决当前该领域的空白 增生性皮损中足细胞丢失触发PECs异常增殖的机制 肾小球疾病。我们项目的长期目标是识别导致PEC的失调通路 在增殖性疾病的发展和/或进展中可能被用作“可用药的”靶点的扩散 肾小球疾病。

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.