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Novel roles of integrin b1 signaling in regulating principal cell function andmaintaining collecting duct integrity

整合素b1信号在调节主要细胞功能和维持集合管完整性中的新作用

基本信息

批准号：
10220019
负责人：
HUA A LU
金额：
$ 37.3万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220019
关键词：
Actins Acute Adult Age Animals Apoptosis CD29 Antigen Cell Adhesion Molecules Cell Cycle Arrest Cell physiology Cells Cues Cultured Cells Cytoskeleton Data Disease Diuresis Duct (organ) structure Ductal Epithelium ECM receptor Endocytosis Epithelial Exocytosis Extracellular Matrix Fibrosis Focal Adhesion Kinase 1 Functional disorder Goals Homeostasis Homo Impairment Inflammation Injury Integrin Signaling Pathway Integrin beta Chains Integrins Kidney Kidney Failure Knockout Mice Mechanics Mediating Mus Mutant Strains Mice Pathology Pathway interactions Physiology Process Recycling Regulation Regulatory Pathway Renal tubule structure Research Role Signal Transduction Structure Transforming Growth Factor beta Transgenic Animals Tubular formation Urine Vasopressins Water Work absorption apical membrane aquaporin-2 base cell injury cell motility cell water collecting tubule structure fibrogenesis hemodynamics integrin-linked kinase interstitial kidney fibrosis mechanotransduction mortality nephrogenesis new therapeutic target novel open data pressure programs response rho GTP-Binding Proteins trafficking transcytosis urinary water channel

项目摘要

The water channel aquaporin-2 (AQP2) is a major water channel that mediates water transport in the collecting ducts (CDs) of the kidney in response to the antidiuretic hormone (ADH), also called vasopressin (VP). We and others have studied extensively the AQP2 trafficking and its regulatory mechanism(s) for many years. In the past 5 years, our studies have uncovered several important and previously unrecognized aspects of AQP2: 1) AQP2 unexpectedly interacts with the adhesion molecule and major extracellular matrix (ECM) receptor, β1 integrin. Through interaction with β1 integrin, AQP2 modulates the trafficking of β1 integrin and promotes tubular cell migration; 2) Polarized AQP2 trafficking to the apical membrane involves basolateral insertion and redirection via transcytosis, and therefore, is potentially subjected to regulatory cues from the ECM; 3) More recently, we have identified that a major downstream target of the integrin signaling pathway, integrin-linked kinase (ILK) regulates AQP2 recycling via modulating the actin cytoskeleton. These data open a novel aspect of a close interplay of AQP2 trafficking and integrin-ECM signaling, and the importance of their interaction in modulating epithelial structure and function. To understand it further, we generated transgenic animals with a deletion of β1 integrin specifically in the principal cells (PCs) in the kidney collecting ducts. Very interestingly, we have found that deleting β1 integrin in the CD PCs causes significant tubular injury and interstitial fibrosis with significantly activated TGF-β signaling cascade. KO mice develop renal failure and early mortality at 6-8 weeks of age. In addition, the young KO and adult hemizygous KO mice presented with highly concentrated urine and impaired capability of water diuresis. There was a significant and persistent apical membrane accumulation of AQP2 in the CD PCs in the homo- and hemizygous β1 integrin KO mice. Based on these two intriguing observations, we proposed a comprehensive research program to 1) determine the critical function of PC specific β1 integrin signaling in maintaining collecting duct integrity, and dissect specifically, the epithelial mechanism(s) contributing to TGF-β activation and subsequent interstitial fibrosis in the β1 integrin KO animals; and 2) characterize the novel regulatory role of β1 integrin signaling in AQP2 trafficking in cells and urine concentration in the kidney. Our proposed studies are logically integrated and focus on two important processes of acute CD injury/fibrosis and water retention. Cross talk between AQP2 and β1 integrin could, therefore, be involved in mediating both cell injury and water reabsorption. They will contribute importantly to better understanding the fundamentally critical, but overlooked epithelial factors that initiate and promote fibrogenesis in kidney. They will also uncover a novel ECM-integrin mediated regulatory mechanism for water transport in the kidney. It could serve as a local regulator of water homeostasis in response to hemodynamic and volume changes.

水通道水通道蛋白-2 （AQP2）是水收过程中调节水分运输的主要水通道