Mechanism of Compensatory Renal Hypertophy

代偿性肾肥大的机制

• 批准号: 8239506
• 负责人: JIAN-KANG CHEN
• 金额: $ 33.93万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239506
• 关键词: 1-Phosphatidylinositol 3-Kinase; Ablation; Amino Acids; Animals; Atrophic; Blood flow; Cell Count; Cell Culture Techniques; Cell Size; Cells; Contralateral; DNA biosynthesis; Data; Development; End stage renal failure; Excision; Fibrosis; Fostering; Genetic Translation; Growth; Homologous Gene; Hyperplasia; Hypertrophy; In Vitro; Injury; Kidney; Kidney Diseases; Leucine; Malignant Neoplasms; Mammalian Cell; Mediating; Mediator of activation protein; Molecular; Mus; Nephrectomy; Nephrons; Operative Surgical Procedures; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Protein Biosynthesis; Proteins; Proximal Kidney Tubules; RNA biosynthesis; Regulation; Regulatory Pathway; Renal Blood Flow; Renal function; Reporting; Research; Research Personnel; Residual state; Ribosomal Protein S6; Role; Secondary to; Signal Pathway; Signal Transduction; Stimulus; Testing; Time; Translation Initiation; Tubular formation; Vacuolar Protein Sorting; Yeasts; attenuation; base; cell growth; human FRAP1 protein; in vivo; injured; interstitial; loss of function; mTOR protein; novel therapeutics; prevent; public health relevance; research study; response

DESCRIPTION (provided by applicant): Reduction of functioning nephron number stimulates increased protein synthesis in the remaining nephron segments, particularly the proximal tubule, leading to increased cell size and mass but not cell number. This type of growth is termed compensatory renal hypertrophy (CRH). CRH occurs not only after surgical renal ablation (secondary to cancer, extremely injured or diseased kidney, or as a kidney donor) but also in virtually all kidney diseases that cause nephron damage and consequently a reduction in the number of functioning nephrons. CRH may actually be a maladaptive response and has been increasingly implicated in fostering further nephron damage, interstitial fibrosis, tubular atrophy and progressive decline of renal function, ultimately leading to end-stage renal disease (ESRD). To date, however, the molecular signals and signaling mechanisms mediating the increased protein synthesis that underlies CRH remain unclear. We have recently reported that CRH is mediated by activation of the mammalian target of rapamycin (mTOR), a central regulator of protein synthesis and cell size control. Our recent preliminary studies revealed that the mTOR signaling activity in renal proximal tubule cells is very sensitive to amino acid load in that amino acid loads activated mTOR signaling within 1 min. Furthermore, we also observed that amino acids activated hVPS34 (the homologue of yeast vacuolar protein sorting defective 34 in mammalian cells) in renal proximal tubule cells. Moreover, our in vivo experiments with mice revealed dramatic activation of hVps34 in the remaining kidney in response to removal of contralateral kidney. In addition, our preliminary data indicate that renal blood flow and free amino acid content are both increased significantly in the remaining kidney as an early response to contralateral nephrectomy. Based on these observations, the specific hypothesis behind the proposed research is that increased delivery of amino acids to the remaining nephron is a growth stimulus that activates hVPS34-dependent mTOR signaling as a major regulatory pathway mediating increased protein synthesis, resulting in CRH. Our long-term objectives are to elucidate the regulatory pathways controlling development of CRH and their potential relationship with progressive renal injury. Our proposed studies for this very first R01 application from a new investigator will have three specific aims for the 5 year time period: Specific Aim #1 will test our hypothesis that following reduction of functioning nephron number, increased delivery of amino acids to the residual functioning nephrons provides a growth stimulus to initiate CRH. Specific Aim #2 is to investigate the role of the 40S ribosomal protein S6 in renal hypertrophy. Specific Aim #3 will identify the upstream mediator of mTOR activation that regulates CRH. PUBLIC HEALTH RELEVANCE: Loss of functioning nephrons stimulates hypertrophic growth of the residual functioning nephrons. This kidney response is known as compensatory renal hypertrophy (CRH). CRH has been increasingly implicated in fostering further nephron damage and progressive decline of renal function, leading to end-stage renal disease (ESRD) but the initial growth signal(s) and molecular signaling mechanism(s) mediating increased protein synthesis that underlies CRH remain unknown. We propose to use combined in vivo and in vitro studies to investigate both upstream and downstream of mTOR activation in CRH.

描述（由申请方提供）：功能性肾单位数量减少刺激剩余肾单位节段（特别是近端小管）中蛋白质合成增加，导致细胞大小和质量增加，但细胞数量不增加。这种类型的生长被称为代偿性肾肥大（CRH）。CRH不仅发生在手术肾消融术后（继发于癌症，严重损伤或患病的肾脏，或作为肾脏供体），而且几乎发生在所有导致肾单位损伤并因此导致功能肾单位数量减少的肾脏疾病中。CRH实际上可能是一种适应不良反应，并且越来越多地涉及促进进一步的肾单位损伤、间质纤维化、肾小管萎缩和肾功能进行性下降，最终导致终末期肾病（ESRD）。然而，迄今为止，介导CRH基础蛋白质合成增加的分子信号和信号传导机制仍不清楚。我们最近报道，CRH是由激活哺乳动物雷帕霉素靶蛋白（mTOR）介导的，mTOR是蛋白质合成和细胞大小控制的中心调节因子。我们最近的初步研究表明，肾近端小管细胞中的mTOR信号活性对氨基酸负荷非常敏感，因为氨基酸负荷在1分钟内激活mTOR信号。此外，我们还观察到氨基酸激活了肾近端小管细胞中的hVPS34（哺乳动物细胞中酵母空泡蛋白分选缺陷34的同源物）。此外，我们对小鼠的体内实验显示，在去除对侧肾脏后，剩余肾脏中的hVps34显著活化。此外，我们的初步数据表明，肾血流量和游离氨基酸含量都显着增加，在剩余的肾脏作为对侧肾切除术的早期反应。基于这些观察结果，提出的研究背后的具体假设是，增加氨基酸向剩余肾单位的递送是一种生长刺激，其激活hVPS34依赖性mTOR信号传导作为介导蛋白质合成增加的主要调控途径，导致CRH。我们的长期目标是阐明控制CRH发展的调控途径及其与进行性肾损伤的潜在关系。我们为新研究者首次申请R01而拟定的研究将在5年时间内有三个具体目标：具体目标#1将检验我们的假设，即在功能肾单位数量减少后，向剩余功能肾单位输送的氨基酸增加，为启动CRH提供了生长刺激。具体目标#2是研究40S核糖体蛋白S6在肾肥大中的作用。具体目标#3将确定调节CRH的mTOR激活的上游介质。 公共卫生相关性：功能性肾单位的丧失刺激残留功能性肾单位的肥大生长。这种肾脏反应被称为代偿性肾肥大（CRH）。CRH越来越多地参与促进进一步的肾单位损伤和肾功能的进行性下降，导致终末期肾病（ESRD），但初始生长信号和介导CRH基础蛋白质合成增加的分子信号传导机制仍然未知。我们建议使用体内和体外联合研究来研究CRH中mTOR激活的上游和下游。