Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks.
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.
Division of Nephrology, University Health Network, McMaster University, Hamilton, Ontario, Canada.
Xuewen
X
Song
Valeria
V
Di Giovanni
Ning
N
He
Kairong
K
Wang
Alistair
A
Ingram
Norman D
ND
Rosenblum
York
Y
Pei
D003560:Cysts / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D049490:Systems Biology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D014157:Transcription Factors