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|العنوان:||Study of Retinoid-X-Receptor-Beta in the Rat Adrenocortical Zona Glomerulosa||المؤلفون:||بشاير خالد الرشيدي Beshayer Alrashidi||Supervisor:||د. بهليند تشنج||الموضوع:||Adrenocortical Zona Glomerulosa adrenal steroidogenesis||تاريخ الاصدار:||2011||الناشر:||Kuwait university - college of graduate studies||ملخص:||The adrenal cortex utilizes cholesterol to synthesize steroid hormones. The zona glomerulosa (ZG) of the cortex manufactures mineralocorticoids, chiefly aldosterone. Aldosterone regulates blood pressure by controlling sodium and potassium homeostasis. Thus, physiologically, either low sodium or high potassium in the circulation stimulates the ZG to produce aldosterone. Disorder in aldosterone metabolism has been linked to development of hypertension. Understanding of the ZG steroidogenesis is crucial for advancement of medical treatment of the disease. Retinoid X receptor (RXR), liver X receptor (LXR) and peroxisome proliferation activator-activated receptor (PPAR) are transcription-activating nuclear receptors, each expressed in α, β and γ isoforms. To exert regulatory function, RXR is commonly heterodimerized with LXR or PPAR. Agonists of RXR, LXR, and PPAR have individually been shown to be useful in the treatment of type-II diabetes, a disease that is associated with hypertension. Because that the human ZG expresses PPARγ, and that the mouse adrenal cortex expresses LXRα and LXRβ, the therapeutic mechanisms are likely to be involved in fine „tuning‟ of syntheses of mineralocorticoids and glucocorticoids. Another ZG-localized nuclear receptor, “Nur-related factor 1” (NURR1), whose role is to regulate aldosterone synthase expression, also has the capability of dimerizing with RXR. Despite of remarkable progress in this field of research, a missing link is the information of RXR in adrenal steroidogenesis. The present investigation was designed to study RXRβ and aldosterone synthase in the ZG of potassium stressed rats, induced by drinking water fortified with 0 (control), 4, 8 and 12% potassium chloride. The new observations are summarized below. a. All the rats that received drinking water fortified with 4, 8 or 12% KCl showed increased potassium in circulation, but failed to gain body weights. Noticeably, only the rats that were treated with 4% KCl showed ZG hypertrophy with co-increases in aldosterone synthase expression and aldosterone synthesis. b. Importantly, rats that received 4% KCl showed increased immunolabeling of RXRβ in the ZG, and elevated RXRβ protein level as confirmed by immunoblotting. Analysis of adrenal unesterified fatty acid composition by gas chromatography/mass spectrometry revealed an increased mol% of docosahexaenoic acid (DHA, C22:6), a potent ligand of RXR. This suggests that the increased RXRβ could be fully activated. Hypothetically, the role of RXRβ in the rat ZG is to regulate aldosterone synthase expression, perhaps in a form of NURR1/RXRβ. In addition, RXRβ could also independently or synchronically dimerize with PPARγ to regulate lipid homeostasis in dealing with potassium stress, although other forms of heterodimerization are also possible. The above findings shed light on our understanding of adrenocortical ZG synthesis of mineralocorticoids, and also serve as an important reference when RXR agonists are contemplated as therapeutic agents to treat type-II diabetes.||URI:||http://hdl.handle.net/123456789/188|
|يظهر في المحتويات:||0540 Medical Biochemistry (M.Sc.)|
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