title: Global identification of the genes and pathways differentially expressed in hypothalamus in early and established neurogenic hypertension.
abstract: The hypothalamus has an important etiological role in the onset and maintenance of hypertension and stress responses in the Schlager high blood pressure (BP) (BPH/2J) mouse, a genetic model of neurogenic hypertension. Using Affymetrix GeneChip Mouse Gene 1.0 ST Arrays we identified 1,019 hypothalamic genes whose expression differed between 6 wk old BPH/2J and normal BP (BPN/3J) strains, and 466 for 26 wk old mice. Of these, 459 were in 21 mouse BP quantitative trait loci. We validated 46 genes by qPCR. Gene changes that would increase sympathetic outflow at both ages were: Dynll1 encoding dynein light chain LC8-type 1, which physically destabilizes neuronal nitric oxide synthase, decreasing neuronal nitric oxide, and Hcrt encoding hypocretin and Npsr1 encoding neuropeptide S receptor 1, each involved in sympathetic response to stress. At both ages we identified genes for inflammation, such as CC-chemokine ligand 19 (Ccl19), and oxidative stress. Via reactive oxygen species generation, these could contribute to oxidative damage. Other genes identified could be responding to such perturbations. Atp2b1, the major gene from genome-wide association studies of BP variation, was underexpressed in the early phase. Comparison of profiles of young and adult BPH/2J mice, after adjusting for maturation genes, pointed to the proopiomelanocortin-α gene (Pomc) and neuropeptide Y gene (Npy), among others, as potentially causative. The present study has identified a diversity of genes and possible mechanisms involved in hypertension etiology and maintenance in the hypothalamus of BPH/2J mice, highlighting both common and divergent processes in each phase of the condition.
authors.affiliation: Basic & Clinical Genomics Laboratory, School of Medical Sciences and Bosch Institute, The University of Sydney, New South Wales, Australia.
authors.forename: Francine Z
authors.initials: FZ
authors.lastname: Marques
authors.forename: Anna E
authors.initials: AE
authors.lastname: Campain
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Davern
authors.forename: Yee Hwa J
authors.initials: YH
authors.lastname: Yang
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Head
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Morris
mesh_terms: D000367:Age Factors; D000818:Animals; D056445:Cytoplasmic Dyneins / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000235:genetics*; D005796:Genes / Q000235:genetics*; D006973:Hypertension / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D009478:Neuropeptide Y / Q000235:genetics; D009479:Neuropeptides / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D000068797:Orexins; D018384:Oxidative Stress / Q000235:genetics; D016133:Polymerase Chain Reaction; D011333:Pro-Opiomelanocortin / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C515062:NPSR1 protein, mouse; D009478:Neuropeptide Y; D009479:Neuropeptides; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D011333:Pro-Opiomelanocortin; D056445:Cytoplasmic Dyneins