Role of Periostin in Polycystic Kidney Disease

骨膜素在多囊肾病中的作用

• 批准号: 7730692
• 负责人: DARREN P. WALLACE
• 金额: $ 36万
• 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/7730692
• 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; Computer Retrieval of Information on Scientific Projects Database; 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（由申请人提供）：常染色体显性多囊肾病（ADPKD）是一种增生性疾病，其中肾小管上皮细胞的异常生长导致形成大量充满液体的囊肿、肾脏大量增大和肾功能进行性丧失。尽管囊肿是良性肿瘤，但它们最终会通过广泛的肾单位损失和纤维化取代邻近的实质而导致肾功能不全。人们对囊肿破坏肾脏的机制知之甚少。然而，细胞外基质（ECM）沉积的变化可能很重要。在培养的人 ADPKD 囊肿上皮细胞的微阵列分析中，与正常人肾 (NHK) 细胞相比，periostin mRNA 过度表达 15 倍。骨膜素最初在成骨细胞中被鉴定为可溶性 ECM 分子，在正常成人肾脏中不表达，但在肾脏发育过程中的肾源区（肾单位形成和血管形成的部位）内短暂表达。在 ADPKD 中，骨膜素在囊肿内衬细胞、囊肿附近的细胞外基质和囊肿液内原位表达。与 NHK 细胞相比，ADPKD 细胞中 aV-整合素（骨膜素受体）的表达高出 9 倍，并且阻断 aV-整合素的抗体可抑制骨膜素诱导的细胞增殖。相比之下，骨膜素不影响正常肾细胞的增殖。我们发现骨膜素可激活整合素连接激酶 (ILK)，这是一种通过激活 Akt、GSK-32/2-catenin 和 mTOR 信号通路来调节细胞增殖和存活的激酶。在初步数据中，我们发现在人类 PKD 模型 pcy/pcy 和 Pkd2WS25/- 小鼠的肾脏中骨膜素表达升高；骨膜蛋白 (PN-/-) 的基因敲除降低了 pcy/pcy 小鼠的肾脏重量（占体重的百分比）。我们还发现，与正常志愿者 (n = 8) 相比，非氮质 ADPKD 患者 (n = 14) 的血清骨膜素水平升高，表明骨膜素可能是 PKD 进展的早期指标。我们的一般假设是骨膜素是一种新型自分泌有丝分裂原，具有加速 ADPKD 囊肿生长和促进间质重塑的潜力。公共健康相关性：ADPKD 是最常见的遗传性肾脏疾病，基因频率为每 500 至 1,000 名新生儿中就有 1 人患有 ADPKD，约占所有终末期肾脏疾病的 5-9%。仅在美国，肾移植、透析和 PKD 相关治疗的费用就接近 20 亿美元/年，预计到本十年末，全球治疗费用将达到 900 亿美元/年。拟议研究的完成将为骨膜素的作用提供新的信息，骨膜素是一种由壁上皮细胞分泌的新型自分泌有丝分裂原，有可能加速 ADPKD 囊肿生长并促进间质重塑。