Mechanism of Compensatory Renal Hypertrophy

描述（由申请人提供）：功能性肾元数目的减少刺激剩余肾元节段，特别是近端肾小管中蛋白质合成的增加，导致细胞大小和质量增加，但细胞数量不增加。这种类型的生长称为代偿性肾肥大（CRH）。CRH不仅发生在手术肾消融后（继发于癌症、严重损伤或病变的肾脏，或作为肾脏供体），也发生在几乎所有肾脏疾病中，这些疾病导致肾元损伤，从而导致功能正常的肾元数量减少。CRH实际上可能是一种适应不良反应，并越来越多地与进一步的肾元损伤、间质纤维化、肾小管萎缩和肾功能进行性下降有关，最终导致终末期肾病（ESRD）。然而，到目前为止，介导CRH下蛋白质合成增加的分子信号和信号机制仍不清楚。我们最近报道了CRH是由哺乳动物雷帕霉素靶蛋白（mTOR）的激活介导的，雷帕霉素靶蛋白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，肾近端小管细胞的mTOR信号活性对氨基酸负荷非常敏感，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液泡蛋白分选缺陷34的同源物）。此外，我们对小鼠进行的体内实验显示，在切除对侧肾脏后，剩余肾脏中的hVps34显著激活。此外，我们的初步数据表明，作为对侧肾切除术的早期反应，剩余肾脏的肾血流量和游离氨基酸含量均显著增加。基于这些观察结果，提出的研究背后的具体假设是，氨基酸向剩余肾单位输送的增加是一种生长刺激，激活hvps34依赖性mTOR信号，作为介导蛋白质合成增加的主要调节途径，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。我们为新研究者的第一个R01申请提出的研究将在5年的时间内有三个具体目标：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输送增加，提供生长刺激以启动CRH。具体目的#2是研究40S核糖体蛋白S6在肾肥大中的作用。具体的Aim #3将确定调控CRH的mTOR激活的上游介质。

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.