Dietary salt has a major impact on blood pressure in many patients and is considered to be an important environmental risk factor for hypertension. Understanding the genetic underpinnings causing hypertensin is a necessary step for developing novel and customized therapeutic strategies for hypertension. We hypothesized that genes important in salt-sensitivity and hypertension might be discovered by identifying genes that undergo changes in abundance in normotensive rats when subjected to a high salt diet-- but do not undergo the same change abundance in rats that become hypertensive on a high salt diet. To distinguish such genes, we applied transcriptional profiling, a powerful new technology in which the abundance of thousands of genes is simultaneously measured, to Sprague Dawley and Dahl salt-sensitive (Dahl SS/Jr) rat strains on 0.4% and 8% NaCI diets. We identified 26 genes that meet this criteria from over 5,000 genes profiled. 2 of these 26 genes, i.e., aminopeptidase N, serum and glucocorticoid inducible kinase-1 (SGK), directly impact on the renin-angiotensin-aldosterone signaling pathway (RAS). The purpose of this proposal is to test the hypothesis that genes for aminopeptidase N and SGK contribute salt-sensitive hypertension in the Dahl rat. Supportive preliminary data shows corresponding changes in abundance of proteins coded for by these genes in the kidneys and that the genes map to known quantitative trait loci (QTLs) for blood pressure.
Aim 1 is to determine whether there is preferential association of specific aminopeptidase N and SGK gene polymorphism(s) in Dahl SS/Jr compared to Dahl salt-resistant (SR/Jr) rat strains.
Specific Aim 2 is to determine whether candidate genes cosegregate with salt-sensitive hypertension.
Specific Aim 3 is to determine salt-sensitivity in congenic Dahl SS/Jr with chromosomal segments from Dahl SR/Jr rats containing SGK and aminopeptidase N genes introgressed. In this Aim, we will develop congenic lines of Dahl SS/Jr introgressed with SR/Jr regions containing aminopeptidase N and SGK genes. This is a first step in the goal of developing novel and customized therapeutic approaches to hypertension based on genetics.
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| Tawar, Urmila; Kotlo, Kumar; Jain, Shilpa et al. (2008) Renal phosphodiesterase 4B is activated in the Dahl salt-sensitive rat. Hypertension 51:762-6 |
| Kotlo, Kumar; Shukla, Sagar; Tawar, Urmila et al. (2007) Aminopeptidase N reduces basolateral Na+ -K+ -ATPase in proximal tubule cells. Am J Physiol Renal Physiol 293:F1047-53 |
| Kotlo, Kumar; Hughes, Douglas E; Herrera, Victoria L M et al. (2007) Functional polymorphism of the Anpep gene increases promoter activity in the Dahl salt-resistant rat. Hypertension 49:467-72 |
