Mechanism of Compensatory Renal Hypertrophy

代偿性肾肥大的机制

• 批准号: 8427380
• 负责人: JIAN-KANG CHEN
• 金额: $ 31.48万
• 依托单位: AUGUSTA 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427380
• 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.

描述(由申请人提供)：功能肾单位数量的减少刺激剩余肾单位部分，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，但不是细胞数量。这种类型的生长称为代偿性肾肥大(CRH)。CRH不仅发生在外科肾切除后(继发于癌症、严重损伤或患病的肾脏，或作为肾脏捐赠者)，而且几乎所有导致肾单位损害的肾脏疾病都会发生CRH，从而导致功能肾单位的数量减少。CRH实际上可能是一种适应不良反应，并且越来越多地参与促进进一步的肾单位损害、间质纤维化、肾小管萎缩和肾功能进行性下降，最终导致终末期肾脏疾病(ESRD)。然而，到目前为止，调节CRH下蛋白质合成增加的分子信号和信号机制仍然不清楚。我们最近报道，CRH是通过激活哺乳动物的雷帕霉素靶标(MTOR)来介导的，mTOR是蛋白质合成和细胞大小控制的中央调节因子。我们最近的初步研究表明，肾近端小管细胞的mTOR信号活性对氨基酸负荷非常敏感，因为氨基酸负荷在1分钟内激活了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离缺陷34的同源物)。此外，我们在小鼠身上的体内实验显示，切除对侧肾脏后，剩余肾脏中hVps34的活性显著增强。此外，我们的初步数据显示，作为对侧肾切除的早期反应，剩余肾脏的肾脏血流量和游离氨基酸含量均显著增加。基于这些观察，这项研究背后的特定假设是，增加氨基酸向剩余肾单位的输送是一种生长刺激，激活hVPS34依赖的mTOR信号，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。我们建议的这项新研究人员首次应用R01的研究将在5年内有三个具体目标：具体目标#1将检验我们的假设，即随着功能肾单位数量的减少，氨基酸向剩余功能肾单位的递送增加提供了启动CRH的生长刺激。具体目的#2是研究40S核糖体蛋白S6在肾脏肥大中的作用。具体目标#3将确定调节CRH的mTOR激活的上游介体。