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Title: Endocrine control of DNA synthesis in renal, adrenal and vascular tissues of the rat in vivo
Author: McEwan, Pauline Erica
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1995
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The aims of this study were firstly to investigate the influence of the renin-angiotensin system on growth of various target tissues (kidney, adrenal gland and blood vessels). Secondly, to determine whether changes in growth were a direct consequence of trophic actions of angiotensin II (AII) or secondary to changes in blood pressure. Thirdly to investigate the interactions of the renin-angiotensin system with other factors (nitric oxide synthesis, glucocorticoid hormone) in the control of growth of target tissues. In each group of rats bromodeoxyuridine (BrdUrd), a thymidine analogue, was given by subcutaneous infusion continuously for two weeks during various treatments. The animals were killed and DNA synthesis was assessed histologically by calculating a BrdUrd index for each cell type. Kidney sections were immunocytochemically stained for renin content. Various morphometric measurements were made in adrenal and vascular tissues. The renin-angiotensin system was manipulated in three ways: i) by infusing AII subcutaneously, ii) by feeding a low or supplemented sodium diet, iii) by administering captopril in the drinking water. The role of nitric oxide in the regulation of DNA synthesis was investigated by treating rats for up to four weeks with an inhibitor of arginine synthase, L-NAME. The effect of glucocorticoid hormone was tested by implanting a dexamethasone pellet subcutaneously. Blood Vessels: In mesenteric blood vessels, AII infusion increased blood pressure and stimulated DNA synthesis in the endothelium, media and adventitia of arteries. Compared with rats fed a sodium supplemented diet, rats given low sodium food had higher BrdUrd indices in all parts of the blood vessels. Captopril lowered the BrdUrd index in the media and adventitia but had no effect on the endothelium. Neither L-NAME nor dexamethasone significantly affected DNA synthesis in vascular smooth muscle cells. DNA synthesis in mesenteric veins was not affected by any treatment. Medial area in transverse sections of arteries was greater after AII treatment. None of the other treatments caused vascular hypertrophy. Adrenal Gland: The BrdUrd indices of epithelial and non-epithelial cells were assessed separately in six areas of the adrenal gland: the zona glomerulosa, the zona intermedia, the outer and inner fasciculata, the zona reticularis and the adrenal medulla. AII and low dietary sodium increased the BrdUrd index significantly in the zona glomerulosa and in the zona reticularis but had no effect on the zona fasciculata. Treatment with captopril caused zona glomerulosa atrophy but had no effect on the BrdUrd index. Captopril reduced DNA synthesis in the reticularis. There was hypertrophy of the zona glomerulosa after treatment with either AII or low sodium whereas, high sodium, L-NAME, dexamethasone and captopril caused atrophy. Changes in the BrdUrd index in the medulla appeared to be controlled in a compensatory manner by blood pressure. Treatments which tend to increase blood pressure (AII, dexamethasone, L-NAME) reduced the BrdUrd index whereas captopril caused an increase. Kidney: The number of renin secreting cells in the kidney was increased by low sodium and also by captopril. Despite the increase in the number of cells, there was no evidence of DNA synthesis in any renin-secreting cell. BrdUrd indices were calculated for glomerular, tubular and interstitial cells. AII increased the BrdUrd index in glomerular cells, captopril caused an decrease but low and high dietary sodium, L-NAME and dexamethasone had no effect. Dexamethasone increased the BrdUrd index in tubule cells and L-NAME increased DNA synthesis in interstitial cells. AII, captopril or dietary sodium manipulation had no effect on DNA synthesis in tubules or interstitial cells. Conclusions: The control of growth of the cardiovascular system is complex, involving direct actions of the renin-angiotensin system. Angiotensin II increases DNA synthesis of many cell types in vivo. Angiotensin II directly regulates DNA synthesis in the adrenal cortex and in blood vessels. Some of the effects of AII are compensatory. Many of the effects of AII on growth are influenced by blood pressure and by interactions with other factors such as nitric oxide and glucocorticoid hormones.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral