Pathways of apoptosis in human autosomal recessive and autosomal dominant polycystic kidney diseases
Pathways of apoptosis in human autosomal recessive and autosomal dominant polycystic kidney diseases
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DOI：
10.1007/s00467-008-0851-9
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发表时间：
2008-09-01
影响因子：
3
通讯作者：
Wilson, Patricia D.
中科院分区：
文献类型：
--
作者：
Goilav, Beatrice;Satlin, Lisa M.;Wilson, Patricia D.
常染色体显性多囊肾病（ADPKD）是成人终末期肾病的主要病因。常染色体隐性（AR） PKD影响约1:20 000活产儿童，围产期死亡率高。这两种疾病都有上皮增生、分泌和细胞-基质相互作用异常，导致进行性囊性扩张和相关间质纤维化。肾脏细胞数量反映了细胞增殖和细胞凋亡之间的平衡。细胞凋亡由外源性（配体诱导的caspase-8的表达）和内源性（线粒体损伤，caspase-9的表达）触发。先前的研究表明细胞凋亡在PKD囊肿形成和实质破坏中的作用。通过年龄匹配的正常组织和PKD组织的定量免疫组织化学和Western免疫印迹分析，研究了人类ADPKD和ARPKD中细胞凋亡的机制。在ADPKD肾脏中，Caspase-8在小囊肿和正常小管中的表达明显高于大囊肿。Caspase-8在ADPKD的发病过程中也较早出现。在ARPKD中，caspase-8的表达在疾病的晚期最为明显，并且不局限于特定的囊肿大小。总之，人类ADPKD中的细胞凋亡是一个早期事件，主要发生在外观正常的小管和小囊肿中，并由外部因素触发，但在ARPKD中发生较晚。
Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage renal disease in adults. Autosomal recessive (AR) PKD affects similar to 1:20,000 live-born children with high perinatal mortality. Both diseases have abnormalities in epithelial proliferation, secretion, and cell-matrix interactions, leading to progressive cystic expansion and associated interstitial fibrosis. Cell number in a kidney reflects the balance between proliferation and apoptosis. Apoptosis results from extrinsic (ligand-induced, expression of caspase-8) and intrinsic (mitochondrial damage, expression of caspase-9) triggers. Previous studies have suggested a role for apoptosis in PKD cyst formation and parenchymal destruction. Mechanisms underlying apoptosis in human ADPKD and ARPKD were examined by quantitative immunohistochemistry and Western immunoblot analyses of age-matched normal and PKD tissues. Caspase-8 expression was significantly greater in small cysts and normal-appearing tubules than in larger cysts in ADPKD kidneys. Caspase-8 also appeared early in the disease process of ADPKD. In ARPKD, expression of caspase-8 was most pronounced in later stages of the disease and was not confined to a specific cyst size. In conclusion, apoptosis in human ADPKD is an early event, occurring predominantly in normal-appearing tubules and small cysts, and is triggered by an extrinsic factor, but it occurs later in ARPKD.