Regulation of Transepithelial Transport in PKD

PKD 中跨上皮转运的调节

• 批准号: 6728704
• 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/6728704
• 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)： 多囊肾病是人类常见的遗传性疾病，具有较高的发病率和死亡率。常染色体显性遗传性PKD(ADPKD)的发病率约为1：1000，而常染色体隐性遗传性PKD(ARPKD)的发病率约为1：20,000。大约50%的ADPKD患者在60岁时发展为终末期肾病(ESRD)，而大多数存活超过围产期的ARPKD婴儿在青春期早期发展为慢性肾功能衰竭。在PKD中，囊肿的生长和扩张破坏了正常的肾实质，并导致肾功能衰竭。在ADPKD中，可以从任何肾小管段产生的囊泡从肾单位“萌芽”出来，不再与其起源的小管相通。相反，ARPKD中的囊肿实际上是扩张性扩张的收集管，它仍然与剩余的肾单位相连，允许尿液继续通过扩张的收集系统流动。 实验ADPKD模型和人类疾病的证据表明，囊的形成和扩张至少部分是由跨上皮溶质和液体分泌引起的。与后一种观察结果相反，我们最近报道ARPKD囊壁上皮是一种钠吸收上皮，至少在疾病早期是这样。跨上皮钠吸收的限速步骤位于心尖上皮钠通道(ENaC)水平，该通道的α和β亚基的稳态水平在ARPKD细胞中高表达。根据这些结果，我们假设ARPKD与钠吸收上调有关，可能是由ENaC介导的，我们推测ENaC参与了高血压的早期发病。 这一假设将通过回答以下具体目标并结合分子、电生理学和功能技术来探索： SAI：探讨ARPKD囊性上皮钠吸收的机制或途径。 SA II：确定那些调节ARPKD囊肿衬里上皮细胞贪婪钠吸收的因素。