Regulation of Transepithelial Transport in PKD

PKD 中跨上皮转运的调节

• 批准号: 6887776
• 负责人: RAJEEV ROHATGI
• 金额: $ 12.77万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887776
• 关键词: cell line; clinical research; electrophysiology; epidermal growth factor; growth factor receptors; human tissue; immunoprecipitation; ion transport; membrane transport proteins; northern blottings; nuclear runoff assay; polycystic kidney; polymerase chain reaction; renal tubular transport; sodium channel; sodium ion; urinary bladder epithelium; voltage /patch clamp; western blottings

DESCRIPTION (provided by applicant): Polycystic kidney disease (PKD) is a common genetic human disease which is associated with a high morbidity and mortality. Autosomal dominant PKD (ADPKD) affects approximately 1: 1,000 people while autosomal recessive PKD (ARPKD) affects approximately 1: 20,000 five births. Approximately 50% of patients with ADPKD develop end-stage renal disease (ESRD) by the sixth decade of life while most infants with ARPKD that survive beyond the perinatal period develop chronic renal failure by early adolescence. In PKD cyst growth and expansion destroys normal renal parenchyma and leads to renal failure. In ADPKD, cysts, which can arise from any tubular segment, "bud" off from the nephron and no longer communicate with the tubule from which they originate. In contrast, cysts in ARPKD are actually ectatic dilated collecting ducts which remain contiguous with the remaining nephron, allowing for urine to continue to flow through the dilated collecting system. Evidence from experimental ADPKD models and human disease suggests that cyst formation and expansion arise, at least in part, from transepithelial solute and fluid secretion. In contrast to the latter observation we have recently reported that ARPKD cyst lining epithelium, at least early in disease, is a Na absorptive epithelium. The rate limiting step in transepithelial Na absorption lies at the level of the apical epithelial Na channel (ENaC) and the steady state levels of the alpha and beta subunits of this channel are highly expressed in ARPKD cells. Based on these results we hypothesize that ARPKD is associated with upregulated Na absorption, presumably mediated by ENaC, which we speculate contributes to the early onset of hypertension. This hypothesis will be explored by answering the following specific aims and using a combination of molecular, electrophysiologic, and functional techniques: SAI: To identify the mechanism or pathway for Na absorption in ARPKD cystic epithelium. SA II: To identify those factors that regulate the avid Na absorption seen in ARPKD cyst lining epithelial cells.

描述（由申请人提供）： 多囊性肾脏疾病（PKD）是一种常见的遗传性人类疾病，与高发病率和死亡率有关。常染色体显性PKD（ADPKD）影响约1：1,000人，而常染色体隐性PKD（ARPKD）影响约1：20,000五个出生。在生命的第六个十年之前，大约50％的ADPKD患者患有终末期肾脏疾病（ESRD），而大多数患有ARPKD的婴儿在围产期超过围产期生存的婴儿会在青春期早期出现慢性肾衰竭。在PKD囊肿生长和膨胀中，会破坏正常的肾实质，并导致肾衰竭。在ADPKD中，可以由任何管状片段引起的囊肿，从肾单位上脱落，而不再与它们起源的肾小管进行通信。相比之下，ARPKD中的囊肿实际上是与剩余的肾单位保持连续的直肠扩张的收集管道，从而使尿液继续流经扩张的收集系统。 实验性ADPKD模型和人类疾病的证据表明，至少部分地来自旋转质溶质和流体分泌的囊肿形成和扩张。与后一个观察结果相反，我们最近报道说，至少在疾病早期的Arpkd囊肿上皮是Na吸收性上皮。 thransepithial Na吸收的速率限制步骤位于顶上上皮Na通道（ENAC）的水平，该通道的alpha和beta亚基的稳态水平在ARPKD细胞中高度表达。基于这些结果，我们假设ARPKD与上调的Na吸收相关，该吸收是由ENAC介导的，我们推测这有助于早期高血压发作。 该假设将通过回答以下特定目的并结合分子，电生理和功能技术来探讨这一假设： SAI：确定ARPKD囊性上皮中Na吸收的机制或途径。 SA II：确定那些调节ARPKD囊肿上皮细胞中AVID NA吸收的因素。