Aldosterone production by adrenal zona glomerulosa (ZG) cells is regulated by the renin-angiotensin system, potassium and, to a lesser extent, ACTH. Sodium depletion leads to an increase in the expression and activity of the enzyme aldosterone synthase. Persistent low salt intake increases the number of ZG cells, as well as aldosterone synthase; ZG cells are """"""""commissioned."""""""" Upon return to a normal salt intake, aldosterone synthase expression decreases. Chronic high sodium intake further decreases aldosterone synthase expression and reduces the number of glomerulosa cells as well, in a process called """"""""decommissioning"""""""" for this proposal. Excessive aldosterone is associated with hypertension, glomerular sclerosis, stroke, and cardiac hypertrophy and fibrosis in humans and experimental animals. Knowledge of the molecular mechanisms involved in ZG decommissioning would guide more effective measures to prevent and treat these diseases.
Aim 1 : ZG decomissioning in Wistar rats that have been subjected to chronic sodium depletion, then acutely repleted with sodium will be studied. The role of apoptosis in the decrease in width of the ZG in decommissioning will be assessed using immunohistochemical (ihc). Real time RT-PCR, Western blots and ihc will be used to demonstrate the role, if any, of genes expressed in the ZG, but not in the rest of the adrenal, that we have recently identified. Changes in gene expression at during decommissioning will be demonstrated using a Laser Capture Microdissection and cDNA microarray technique used successfully by us before, clones will be verified, then mRNA and protein levels for candidate genes, those with the greatest changes and or recognized as being involved in major cell regulatory processes will be studied.
Aim 2 : Study the ZG in the SHR-SP during chronic sodium loading when the expression of aldosterone synthase in this strain of rat increases, rather than decreases as in normal individuals. Using similar protocols as those in Aim 1, we will study and compare the process of adrenal decommissioning between SHR-SP and regular SHR rats with emphasis of the ZG genes identified as important in Aim 1.
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