Role of Periostin in Polycystic Kidney Disease

骨膜素在多囊肾病中的作用

• 批准号: 8129499
• 负责人: DARREN P. WALLACE
• 金额: $ 31.98万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-21 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8129499
• 关键词: Accounting; Adult; Affect; Animals; Area; Autosomal Dominant Polycystic Kidney; Benign; Binding; Birth; Blocking Antibodies; Blood Urea Nitrogen; Body Weight; Cell Line; Cell Proliferation; Cell Survival; Cells; Complex; Cyst; Cyst Fluid; Cystic kidney; Data; Deposition; Development; Dialysis procedure; Disease; Disease Progression; End stage renal failure; Epithelial Cells; Extracellular Matrix; Female; Fibrosis; Focal Adhesion Kinase 1; Focal Adhesions; Gene Frequency; Genetic; Goals; Growth; Histology; Human; Hyperplasia; Image; In Situ; Inherited; Integrins; Investigation; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knock-out; Knockout Mice; Liquid substance; Magnetic Resonance Imaging; Measures; Mediating; Messenger RNA; Microarray Analysis; Mitogens; Molecular; Mus; Neoplasms; Nephrons; Osteoblasts; Pathway interactions; Patients; Pattern; Phosphotransferases; Polycystic Kidney Diseases; Renal function; Research Project Grants; Role; Serum; Site; Urine; Vascularization; Weight; autocrine; cancer cell; cost; human FRAP1 protein; indexing; integrin-linked kinase; interstitial; kidney cell; mTOR Signaling Pathway; male; mouse model; novel; periostin; public health relevance; receptor; src-Family Kinases; volunteer

DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is a hyperplastic disorder in which aberrant growth of tubule epithelial cells causes the formation of numerous fluid-filled cysts, massively enlarged kidneys and progressive loss of renal function. Although cysts are benign neoplasms, they ultimately cause renal insufficiency through extensive nephron loss and replacement of adjacent parenchyma with fibrosis. The mechanisms by which cysts destroy the kidneys are poorly understood; however changes in the deposition of the extracellular matrix (ECM) are likely to be important. In a microarray analysis of cultured human ADPKD cyst epithelial cells, periostin mRNA was over expressed 15-fold compared to normal human kidney (NHK) cells. Periostin, initially identified in osteoblasts as a soluble ECM molecule, is not expressed in normal adult kidneys but is expressed transiently during renal development within the nephrogenic zone, a site of nephron formation and vascularization. In ADPKD, periostin was expressed in cyst-lining cells in situ, in extracellular matrix adjacent to the cysts and within cyst fluid. Expression of aV-integrin, a receptor for periostin, was 9-fold higher in ADPKD cells compared to NHK cells, and antibodies that block aV-integrin inhibited periostin-induced cell proliferation. By contrast, periostin did not affect the proliferation of normal kidney cells. We found that periostin activates integrin-linked kinase (ILK), a kinase that regulates cell proliferation and survival through activation of Akt, GSK-32/2-catenin and mTOR signaling pathways. In preliminary data, we found that periostin expression was elevated in the kidneys of pcy/pcy and Pkd2WS25/- mice, models of human PKD; and that genetic knockout of periostin (PN-/-) reduced kidney weight (as a % of body weight) in the pcy/pcy mouse. We also found that periostin levels were elevated sera of non-azotemic ADPKD patients (n = 14) compared to normal volunteers (n = 8), suggesting that periostin may be an early indicator of PKD progression. Our general hypothesis is that periostin is a novel autocrine mitogen with the potential to accelerate cyst growth and promote interstitial remodeling in ADPKD. PUBLIC HEALTH RELEVANCE: ADPKD is the most frequently inherited kidney disorder with a gene frequency of 1 in 500 to 1,000 births and accounts for approximately 5-9% of all end-stage renal diseases. Costs for renal transplantation, dialysis and related treatments for PKD approach $2 billion/yr in the US alone and it is estimated that by the end of this decade treatments will cost $90 billion/yr worldwide. Completion of the proposed studies will provide new information on the role of periostin, a novel autocrine mitogen secreted by mural epithelial cells with the potential to accelerate cyst growth and promote interstitial remodeling in ADPKD.

描述(申请人提供)：常染色体显性遗传性多囊肾病(ADPKD)是一种增生性疾病，肾小管上皮细胞异常生长导致大量充满液体的囊肿形成，肾脏大量增大和进行性肾功能丧失。虽然囊肿是良性肿瘤，但它们最终会通过广泛的肾单位丢失和以纤维化取代邻近实质而导致肾功能不全。包囊破坏肾脏的机制尚不清楚；然而，细胞外基质(ECM)沉积的变化可能是重要的。在培养的人ADPKD囊上皮细胞的微阵列分析中，Periostin mRNA的过度表达是正常人类肾脏(NHK)细胞的15倍。Periostin最初在成骨细胞中被鉴定为一种可溶的ECM分子，在正常成人肾脏中不表达，但在肾形成区的肾脏发育过程中短暂表达，肾原区是肾单位形成和血管形成的地方。在ADPKD中，Periostin表达于原位的囊壁细胞、邻近囊壁的细胞外基质和囊液中。在ADPKD细胞中，Periostin的受体AV-整合素的表达是NHK细胞的9倍，并且阻断AV-整合素的抗体抑制了Periostin诱导的细胞增殖。相比之下，Periostin并不影响正常肾细胞的增殖。我们发现Periostin通过激活Akt、GSK-32/2-catenin和mTOR信号通路激活整合素连接的激酶(ILK)，调节细胞的增殖和存活。在初步数据中，我们发现Periostin在人类PKD模型pcy/pcy和Pkd2WS25/-小鼠的肾脏中表达升高；基因敲除Periostin(Pn-/-)降低了pcy/pcy小鼠的肾脏重量(占体重的百分比)。我们还发现非氮质型ADPKD患者(n=14)的血清Periostin水平高于正常志愿者(n=8)，提示Periostin可能是PKD进展的早期指标。我们的一般假设是，Periostin是一种新的自分泌有丝分裂原，具有加速ADPKD囊性生长和促进间质重塑的潜力。公共卫生相关性：ADPKD是最常见的遗传性肾脏疾病，其基因频率为每500至1000名新生儿中有1人，约占所有终末期肾脏疾病的5%至9%。仅在美国，肾移植、透析和相关治疗PKD的费用就接近20亿美元/年，据估计，到本十年末，全球治疗费用将达到900亿美元/年。这些研究的完成将为研究Periostin的作用提供新的信息。Periostin是一种由壁上皮细胞分泌的新的自分泌有丝分裂原，具有加速ADPKD囊性生长和促进间质重塑的潜力。