Blood Pressure Control Determined by Chromosome 13

Medical College Of Wisconsin, Milwaukee WI

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Abstract

The goal of Project by Cowley is to use physiological and gene microarray expression data to determine how genes[unreadable] within four discrete regions of Chromosome 13 (Chr 13) initiate and/or maintain the cascade of events[unreadable] determining blood pressure salt-sensitivity and renal dysfunction in the Dahl S (SS) rat. As shown previously,[unreadable] introgression of the entire Chr 13 from the inbred Brown Norway (BN) strain of rat into the genomic background[unreadable] of the SS rat strain (consomic SS-13BN) substantially reduces salt-induced hypertension and proteinuria. We[unreadable] have now completed development of and have phenotyped 23 congenic inbred strains with overlapping BN[unreadable] Chr 13 chromosomal segments introgressed into SS. Four discrete congenic regions of these BN substitutions[unreadable] within the SS genomic background (congenic strains 1, 5, 9 and 26), that range in size from 4.5 to 16 Mbp[unreadable] resulted in significant protection from salt-induced hypertension in female rats. Reductions of the levels of[unreadable] hypertension ranged from 22 to 32 mmHg among these congenic strains. In addition, since sex differences[unreadable] affected the degree of protection from salt-induced hypertension in several of the .congenic strains, one of[unreadable] these strains (congenic strain 9) was selected to determine variations of genomic and physiological pathways[unreadable] that may explain these male and-female differences. We hypothesize that genes within these four congenic[unreadable] regions of Chr 13 collectively contribute to genome-wide responses and operate through shared functional[unreadable] pathways to improve the sodium excretory function of the kidney and thereby protect the organism from salt-induced[unreadable] hypertension. Three systems important in the regulation of sodium homeostasis and arterial pressure[unreadable] regulation will be assessed, the kidneys (cortex and medulla), the adrenals (reflecting autonomic and[unreadable] endocrine function) and the vasculature. Studies in Aim I will determine the sequential physiological changes[unreadable] in pathways under conditions of 0.4% salt diet and at 16 hr, 3 and 12 days after switching to a 4.0% salt diet.[unreadable] Aim 2 will utilize gene microarrays as a powerful assay system to identify pathways and networks that are[unreadable] linked to whole system physiology. Molecular profiles reflected by mRNA expression will be combined with[unreadable] physiological profiles obtained in Aim 1 in an integrative'analysis to identify the molecular patterns and[unreadable] pathways that underlie common physiological systems responsible for the phenotypic differences .between the[unreadable] SS rat and'the reduced salt-sensitivity of the congenic strains. >Even if little is currently known of the function of[unreadable] a differentially expressed gene, gene function can be reverse engineered by placing .them into the context of[unreadable] an overall functional pathway to predict gene-function relationships. The use of congenic strains within Chr 13[unreadable] with well-defined blood pressure phenotypes provides a unique opportunity to produce an integrated picture of[unreadable] how genes within four discrete regions of Chr 13 modify salt-induced hypertension. This may provide valuable[unreadable] clues to define these critical pathways responsible for salt-induced forms of hypertension in human subjects,[unreadable] especially in high risk populations such as African-Americans.