Importance of cell-matrix interactions in kidney repair after acute kidney injury

细胞-基质相互作用在急性肾损伤后肾脏修复中的重要性

基本信息

批准号：
10585440
负责人：
Dong Zhou
金额：
$ 50.19万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585440
关键词：
3-Dimensional Acute Renal Failure with Renal Papillary Necrosis Affect Attention Binding Biological Cell Death Cell Proliferation Cells Cessation of life Chronic Kidney Failure Complex Creatinine Data Deterioration Development Disease Environment Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Glycoproteins Growth Factor Hospitalization In Vitro Incubated Inflammatory Injury to Kidney Investigation Ischemia Kidney Knockout Mice Macrophage Maintenance Mediating Modeling Output Pathogenesis Peptides Process Proteins Proteomics Regimen Renal function Renal tubule structure Repression Research Risk Role SHH gene Serum Shapes Signal Transduction Source System Techniques Testing Treatment Efficacy Tubular formation Urine cell type conditional knockout design in vivo injured injury and repair insight interstitial kidney cell kidney repair knock-down long-term sequelae new therapeutic target novel novel therapeutic intervention novel therapeutics overexpression prevent recruit renal ischemia repaired scaffold tumorigenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI) is characterized by abrupt deterioration in kidney function, manifested by an increase in serum creatinine level, with or without a reduction in the amount of urine output. Tragically, between 2009- 2019, hospitalizations in the US complicated by AKI increased by 42%. The long-term objectives of this application are to better understand the kidney local microenvironment and its impact on AKI with an eye towards development of new treatment strategies. The AKI research field believes that renal tubules are the epicenter of damage, yet little attention has been paid to changes in the renal local microenvironment and associated repair processes, which are certain to impact AKI. The concept of a ‘microenvironment’ has shaped the understanding of the pathogenesis of various diseases. However, the AKI microenvironment is poorly characterized. The kidney local microenvironment in AKI - consisting of injured tubular cells, activated fibroblasts, inflammatory cells (e.g., macrophages), other cellular components, extracellular matrix (ECM), and a variety of secreted factors - is complex, heterotypic, and dynamic. After AKI, in general, renal tubules undergo a repair process of dedifferentiation. During this process, ECM is the major organizing component for microenvironment construction and tubule repair, serving as a scaffold for remodeling. The major cellular source of ECM synthesis in the kidney is interstitial fibroblasts. Several subpopulations of fibroblasts are activated exceptionally early after AKI (1h), far earlier than tubular cell proliferation (3d). This suggests that fibroblast-derived proteins may act early in AKI. To explore this idea in depth, matrix proteins were compared between AKI and control kidneys using ischemic kidney models and proteomics. This identified extracellular matrix protein 1 (ECM1; a secreted glycoprotein) as the earliest and highest activated matrix protein after ischemic AKI. ECM1 was induced rapidly (4-8h) after AKI and localized predominantly to fibroblast-rich foci in the kidney interstitium. It was also found that after AKI, Sonic Hedgehog (Shh) growth factor secreted by renal tubules specifically targets fibroblasts to mediate cell-matrix interactions. Further study revealed that ECM1 binds to Shh in vitro, knockdown of ECM1 aggravates AKI in vivo, and ECM1 peptide prevents tubular cell death in vitro. Based on these observations and the role of macrophages in microenvironment formation, it was hypothesized that after AKI, ECM1 directly recruits Shh, which activates fibroblasts and macrophages to form a favorable microenvironment to promote kidney remodeling. This hypothesis will be tested by determining the mechanistic role of ECM1 in kidney microenvironment formation ex vivo (Aim 1); determining the roles of injured tubules, activated fibroblasts, and macrophages in constructing the kidney microenvironment after AKI (Aim 2); and determining the role of the ECM1-organized cell-matrix interactions in promoting AKI repair in vivo (Aim 3). Our investigations have broad implications for elucidating mechanisms for kidney repair and designing novel therapeutic regimens to prevent or mitigate AKI.

项目概要/摘要急性肾损伤（AKI）的特点是肾功能突然恶化，表现为肾功能增加悲惨的是，从 2009 年到 2019 年，美国因 AKI 住院的人数增加了 42% 这是长期目标。应用程序是为了更好地了解肾脏局部微环境及其对 AKI 的影响，着眼于开发新的治疗策略 AKI 研究领域认为肾小管是 AKI 的中心。损伤，但很少关注肾脏局部微环境的变化和相关修复 “微环境”的概念塑造了人们对 AKI 的理解。然而，AKI 微环境的特征尚不清楚。 AKI 中的局部微环境 - 由受损的肾小管细胞、活化的成纤维细胞、炎症细胞（例如，巨噬细胞）、其他细胞成分、细胞外基质（ECM）和各种分泌因子 - 是一般来说，AKI 后肾小管会经历一个复杂的、异型的和动态的修复过程。在此过程中，ECM是微环境构建的主要组织成分。和肾小管修复，作为肾脏重塑的支架 ECM 合成的主要细胞来源。间质成纤维细胞的几个亚群在 AKI 后（1 小时）非常早地被激活。早于肾小管细胞增殖 (3d)，这表明成纤维细胞衍生的蛋白可能在 AKI 早期发挥作用。为了深入探讨这一想法，使用缺血性肾病模型对 AKI 肾脏和对照肾脏之间的基质蛋白进行了比较肾脏模型和蛋白质组学鉴定了细胞外基质蛋白 1（ECM1；一种分泌性糖蛋白）。缺血性 AKI 后最早且最高活化的基质蛋白 ECM1 在 AKI 后迅速（4-8 小时）被诱导。并且主要定位于肾间质中富含成纤维细胞的病灶。还发现，在 AKI 后，Sonic 会发生变化。肾小管分泌的刺猬 (Shh) 生长因子专门针对成纤维细胞介导细胞基质进一步的研究表明，ECM1 在体外与 Shh 结合，在体内 ECM1 的敲低会加重 AKI。根据这些观察结果以及巨噬细胞的作用，ECM1 肽可在体外预防肾小管细胞死亡。在微环境形成中，AKI后ECM1直接招募Shh，从而激活成纤维细胞和巨噬细胞形成有利的微环境，促进肾脏重塑。通过确定 ECM1 在肾脏微环境形成中的机制作用来检验假设体内（目标 1）；确定受损肾小管、活化成纤维细胞和巨噬细胞在构建 AKI 后的肾脏微环境（目标 2）；并确定 ECM1 组织的细胞基质的作用促进体内 AKI 修复的相互作用（目标 3）。肾脏修复机制并设计新的治疗方案来预防或减轻 AKI。