New insights into ADPKD molecular pathways using combination of SAGE and microarray technologies.
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the PKD1 or PKD2 gene, but cellular mechanisms of cystogenesis remain unclear. In an attempt to display the array of cyst-specific molecules and to elucidate the disease pathway, we have performed comprehensive high-throughput expression analysis of normal and ADPKD epithelia in a two-step fashion. First, we generated expression profiles of normal and cystic epithelia derived from kidney and liver using serial analysis of gene expression (SAGE). We found 472 and 499 differentially expressed genes with fivefold difference in liver and kidney libraries, respectively. These genes encode growth factors, transcription factors, proteases, apoptotic factors, molecules involved in cell-extracellular matrix interactions, and ion channels. As a second step, we constructed a custom cDNA microarray using a subset of the differentially regulated genes identified by SAGE and interrogated ADPKD patient samples. Subsequently, a set of differentially expressed genes was refined to 26 up-regulated and 48 down-regulated genes with ap value of <0.01. This study may provide valuable insights into the pathophysiology of ADPKD and suggest potential therapeutic targets.
Husson
Hervé
H
Functional Genomics, Genzyme Corporation, Framingham, MA 01701-9322, USA.
Manavalan
Partha
P
Akmaev
Viatcheslav R
VR
Russo
Ryan J
RJ
Cook
Brian
B
Richards
Brenda
B
Barberio
Dana
D
Liu
Dongyu
D
Cao
Xiaohong
X
Landes
Gregory M
GM
Wang
Clarence J
CJ
Roberts
Bruce L
BL
Klinger
Katherine W
KW
Grubman
Shelley A
SA
Jefferson
Douglas M
DM
Ibraghimov-Beskrovnaya
Oxana
O
D000704:Analysis of Variance; D017931:DNA Primers; D004848:Epithelium / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D015723:Gene Library; D005796:Genes / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers