Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks

被引:202
作者
Song, Xuewen [1 ]
Di Giovanni, Valeria [2 ]
He, Ning [1 ]
Wang, Kairong [1 ]
Ingram, Alistair [3 ]
Rosenblum, Norman D. [2 ]
Pei, York [1 ]
机构
[1] McMaster Univ, Div Nephrol, Univ Hlth Network, Hamilton, ON, Canada
[2] McMaster Univ, Hosp Sick Children, Program Dev & Stem Cell Biol, Hamilton, ON, Canada
[3] McMaster Univ, Div Nephrol, Hamilton, ON, Canada
基金
加拿大健康研究院;
关键词
SERUM RESPONSE FACTOR; BETA-CATENIN; INHIBITION SLOWS; NUCLEAR FACTOR; CELL-CYCLE; RECEPTOR; KLOTHO; MODEL; CYSTOGENESIS; PROGRESSION;
D O I
10.1093/hmg/ddp165
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
To elucidate the molecular pathways that modulate renal cyst growth in ADPKD, we performed global gene profiling on cysts of different size (< 1 ml, n = 5; 10-20 ml, n = 5; > 50 ml, n = 3) and minimally cystic tissue (MCT, n = 5) from five PKD1 human polycystic kidneys using Affymetrix HG-U133 Plus 2.0 arrays. We used gene set enrichment analysis to identify overrepresented signaling pathways and key transcription factors (TFs) between cysts and MCT. We found down-regulation of kidney epithelial restricted genes (e.g. nephron segment-specific markers and cilia-associated cystic genes such as HNF1B, PKHD1, IFT88 and CYS1) in the renal cysts. On the other hand, PKD1 cysts displayed a rich profile of gene sets associated with renal development, mitogen-mediated proliferation, cell cycle progression, epithelial-mesenchymal transition, hypoxia, aging and immune/inflammatory responses. Notably, our data suggest that up-regulation of Wnt/beta-catenin, pleiotropic growth factor/receptor tyrosine kinase (e.g. IGF/IGF1R, FGF/FGFR, EGF/EGFR, VEGF/VEGFR), G-protein-coupled receptor (e.g. PTGER2) signaling was associated with renal cystic growth. By integrating these pathways with a number of dysregulated networks of TFs (e.g. SRF, MYC, E2F1, CREB1, LEF1, TCF7, HNF1B/ HNF1A and HNF4A), our data suggest that epithelial dedifferentiation accompanied by aberrant activation and cross-talk of specific signaling pathways may be required for PKD1 cyst growth and disease progression. Pharmacological modulation of some of these signaling pathways may provide a potential therapeutic strategy for ADPKD.
引用
收藏
页码:2328 / 2343
页数:16
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