A key concept in the field of essential hypertension research is that the genetic transmission of increased blood pressure (BP) is determined by the genotype of the kidney. To investigate this problem, a powerful strategy of kidney specific gene transfer (KSGT) has been developed that enables the selective intrarenal exchange of single chromosome regions between the spontaneous hypertensive rat (SHR) and congenic strains of SHR that are genetically identical except for specific chromosome regions derived from the normotensive Brown Norway (BN) rat. By applying this technique in a congenic strain of SHR that carries a defined segment of BN chromosome 1, a specific region of BN chromosome 1 has been isolated that can attenuate hypertension when selectively expressed inside the kidney of the SHR. In the current studies, we will search for renally expressed genes within this chromosome region that contribute to the pathogenesis of spontaneous hypertension. We will investigate 2 alternative hypotheses using complementary strategies as follows: Hypothesis 1: A hypertension gene exists within the target segment of chromosome 1 that is differentially expressed between the kidneys of the SHR and the SHR.BN-Igf2 congenic strain (the SHR congenic strains). To identify such genes, cDNA microarray technology will be used to perform gene expression profiling of kidneys obtained from the SHR and the SHR congenic strains. Novel strategies of KSGT will be used to insure that differences in the renal expression of genes between the SHR and the SHR congenic strain are not simply secondary to hemodynamic or metabolic differences between these two strains. Hypothesis 2. A hypertension gene exists within the target segment of chromosome 1 that is not differentially expressed between the kidneys of the SHR and the SHR congenic strain. To allow for this alternative hypothesis, we will also narrow the location of the hypertension gene by meiotic mapping analysis of a segregating F2 population derived from the SHR progenitor strain and the SHR congenic strain that carries the target region of chromosome 1 from the BN strain. Under this alternative hypothesis, the results of the cDNA microarray analysis will be used to identify potential downstream target genes whose expression is altered by the primary genetic defect on chromosome 1.
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