Neuroendocrine transcriptome in genetic hypertension: multiple changes in diverse adrenal physiological systems.
The genetic basis of hypertension in the genetically/hereditary hypertensive (BPH/2) mouse strain is incompletely understood, although a recent genome scan uncovered evidence for several susceptibility loci. To probe the neuroendocrine transcriptome in this disease model, 12 488 probe set microarray experiments were performed on mRNA transcripts from adrenal glands of juvenile (prehypertensive) and adult BPH/2 (hypertensive), as well as the genetically/hereditary low-blood pressure (BPL/1), strains at both time points. To determine the impact of strain (BPH/2 versus BPL/1), age (juvenile versus adult), and the interaction of strain and age on gene expression levels, we performed standard 2-factor ANOVA and computed a concordance coefficient to assess the reproducibility of gene expression measurements among replicates. Of genes with significant (P<0.05) differential expression, 2647 showed strain differences, 982 showed age differences, and 757 exhibited strain-by-age interaction. Fold-changes in gene expression assayed by microarray were confirmed in a subset by real-time polymerase chain reaction (R=0.739, P=0.0094). We used a systems biology approach to evaluate alterations in contributing biochemical pathways and we statistically quantified these global pathway disturbances using the Kolmogorov-Smirnov goodness-of-fit test. We found widespread, indeed global, alterations in patterns of gene expression in diverse systems of BPH/2: in sympathochromaffin transcripts suggesting increased sympathetic stimulation; in vasoconstrictor/vasodilator systems; global reductions in carbohydrate intermediary metabolism; and increases in oxidative stress, with changes in oxygen radical forming and disposition enzymes. These analyses highlight widespread derangements in diverse physiological pathways, providing multiple avenues for further investigation into the pathogenesis of genetic hypertension.
Fries
Ryan S
RS
Department of Bioengineering, University of California at San Diego, San Diego, Calif 92161, USA.
Mahboubi
Payam
P
Mahapatra
Nitish R
NR
Mahata
Sushil K
SK
Schork
Nicholas J
NJ
Schmid-Schoenbein
Geert W
GW
O'Connor
Daniel T
DT
D000311:Adrenal Glands / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D003433:Crosses, Genetic; D020869:Gene Expression Profiling; D006973:Hypertension / Q000235:genetics*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D014176:Protein Biosynthesis; D011506:Proteins / Q000145:classification / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D011506:Proteins; D012333:RNA, Messenger