title: Common genetic mechanisms of blood pressure elevation in two independent rodent models of human essential hypertension.
abstract: Genetic studies of essential hypertension, a complex, polygenic, and age-dependent disorder, have not been able to completely elucidate the genes responsible for development of the trait. We used a novel strategy to compare gene expression in the adrenal gland of two independent rodent models of human essential hypertension (the spontaneously hypertensive rat, SHR, and the blood pressure high mouse, BPH), with the goal of uncovering shared, common genetic mechanisms of hypertension across mammalian species that might, therefore, be pertinent to human hypertension. We deliberately studied young, 4- to 5-week-old, "prehypertensive" SHR and BPH that had not yet developed complete elevations in blood pressure (BP), so that we could minimize the impact of chronic, sustained BP elevation, age, and other confounding factors on gene expression, therefore increasing the likelihood that differential expression reflects relatively early pathogenic mechanisms in hypertension, rather than later responses to, or compensations for BP elevation. We compared transcript expression patterns of genes orthologous between the rat and the mouse, and presented candidate genes for hypertension that are differentially expressed in the same direction in SHR and BPH (ie, overexpressed in both SHR and BPH, or underexpressed in both SHR and BPH). Then we used a systems biology approach to analyze expression patterns in biochemical pathways and networks to isolate systems involved in hypertension pathology in both SHR and BPH. We found transcript pattern evidence for involvement of several systems in the pathology of hypertension in SHR and BPH: adrenal catecholamines and sympathetic function; steroid hormone synthesis, catabolism, and its contribution to enhanced glucocorticoid sensitivity in SHR; oxidative stress and its role as a common mechanism of vascular and end-organ injury; and intermediary metabolism with global but mechanistically different perturbations in SHR and BPH. Approximately 10% of the differentially expressed orthologous genes we studied shared a common direction of expression in the two hypertensive rodent strains, suggesting fundamental transcriptional mechanisms in common whereby mammals can elevate BP or respond to such elevation; even these shared orthologs spanned a diverse set of biological processes, reinforcing the multifactorial and complex nature of hypertension.
authors.affiliation: Department of Bioengineering, San Diego, California 92093-0838, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Friese
authors.forename: Payam
authors.initials: P
authors.lastname: Mahboubi
authors.forename: Nitish R
authors.initials: NR
authors.lastname: Mahapatra
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Geert W
authors.initials: GW
authors.lastname: Schmid-Schönbein
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D002395:Catecholamines / Q000096:biosynthesis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013256:Steroids / Q000096:biosynthesis; D013564:Sympathetic Nervous System / Q000502:physiology
chemical_list: D002395:Catecholamines; D017382:Reactive Oxygen Species; D013256:Steroids