Bailey, Matthew

Dhaun, Neeraj

Livingstone, Dawn

Costello, Hannah Mhairi

other

2021-10-12T09:58:59Z

2021-10-12T09:58:59Z

2021-07-31

Salt-sensitive blood pressure (BP) reflects underlying renal salt excretion impairment, suggesting compromised pressure natriuresis (PN) relationship, and vascular (endothelial) dysfunction. People with abnormal glucocorticoid homeostasis, such as in Cushing’s syndrome, are often salt-sensitive but the underlying mechanisms are not clearly defined. Evidence has suggested abnormal glucocorticoid activity, via dysregulation of hypothalamic pituitary adrenocortical (HPA) axis, may have a major contributory role in salt-sensitivity. Therefore, I hypothesised that glucocorticoid excess causes vascular and renal dysfunction, contributing to salt-sensitive hypertension. I tested this hypothesis in a mouse model of ACTH-dependent Cushing’s syndrome. BP was measured longitudinally in adult male C57BL/6JCrl mice by radiotelemetry, examining the effect of high salt diet (3% sodium) before and after chronic ACTH treatment. I found underlying salt-sensitivity in C57BL/6JCrl mice: BP increased by ~12 mmHg following the transition from a control salt diet (0.3% sodium) to high salt diet. Following washout, ACTH was infused by osmotic minipump, which increased daytime BP (inactive phase), flattening the diurnal BP rhythm. Reintroduction of high salt diet amplified salt-sensitivity, increasing BP ~20 mmHg. To investigate underlying mechanisms of salt-sensitivity, the acute PN relationship and vascular function were assessed in ACTH-treated mice. The acute PN relationship was unaltered with glucocorticoid excess before and after a high salt challenge. The sensitivity and maximal contractile response to vasoconstrictor phenylephrine was significantly reduced in renal arteries following glucocorticoid excess before and after a high salt challenge, with no change in mesenteric arteries. The sensitivity and maximal dilatory response to both endothelium-dependent and -independent vasodilators was reduced in renal arteries, with no changes in mesenteric arteries. Messenger RNA (mRNA) levels of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) were assessed in renal arteries. Chronic glucocorticoid excess decreased GR but not MR mRNA in the renal artery, suggesting that glucocorticoids are primarily acting via MR in the renal artery. Therefore, I hypothesised antagonism of the MR could be protective. The effect of MR blockade (20 mg/kg/day spironolactone) on BP and vascular function following glucocorticoid excess and high salt was measured. MR blockade did not change BP but rescued the renal artery dysfunction. In other experiments, I assessed the effect of high salt diet on plasma glucocorticoid levels. High salt treatment in male C57BL/6JCrl mice increased plasma glucocorticoids. High salt also increased plasma copeptin levels, suggesting elevation of AVP. Activation of magnocellular AVP-secreting neurons could bypass glucocorticoid feedback and support sustained activation of the HPA axis. Additionally, high salt decreased hippocampal MR mRNA expression which could have implications on the tone of the HPA axis. Consistent with this, restraint test sensitivity was amplified in C57BL/6JCrl mice. In conclusion, I found a reciprocal relationship between glucocorticoids and salt. Underlying glucocorticoid excess induces renal vasodysfunction and amplifies salt-sensitive BP response. Furthermore, high salt induces activation of the HPA axis. Together, this could have long-term implications on the stress response and salt-sensitivity.

https://hdl.handle.net/1842/38150

http://dx.doi.org/10.7488/era/1417

en

The University of Edinburgh

Costello, H.M., Stewart, K, Jones, N.K., Grenier, C, Angel, S, Ralph, A.F., Holmes, M.C., Livingstone, D.E.W., Dhaun, N, Bailey, M.A. Glucocorticoid excess induces renal vascular dysfunction and amplifies salt-sensitive hypertension. APS/ASN Conference: Control of Renal Function in Health and Disease, Charlottesville, USA 2019

.F., Holmes, M.C., Livingstone, D.E.W., Dhaun, N, Bailey, M.A. Glucocorticoid excess induces renal vascular dysfunction and amplifies salt-sensitive hypertension. Early career researcher oral presentation award, CVS Symposium, Edinburgh, UK 2019

Costello, H.M., Stewart, K, Jones, N.K., Grenier, C, Livingstone, D.E.W., Dhaun, N, Bailey, M.A. Mechanisms behind salt-sensitivity in a mouse model of ACTH-dependent Cushing’s syndrome. Experimental Biology, Orlando, USA 2019

Costello, H.M., Stewart, K, Jones, N.K., Grenier, C, Livingstone, D.E.W., Dhaun, N, Bailey, M.A. Mechanisms behind salt-sensitivity in a mouse model of ACTH-dependent Cushing’s syndrome. Pre-EB Epithelial Transport meeting, Orlando, USA 2019

Costello, H.M., Stewart, K, Jones, N.K., Livingstone, D.E.W., Dhaun, N, Bailey, M.A. Impairment of pressure natriuresis in a mouse model of ACTH-dependent Cushing’s Syndrome. ESAC Symposium, Erlangen, Germany 2018

Costello, H.M., Stewart, K, Jones, N.K., Livingstone, D.E.W., Dhaun, N, Bailey, M.A. Impairment of pressure natriuresis in a mouse model of ACTH-dependent Cushing’s Syndrome. Europhysiology, London, UK 2018

Czopek, A, Moorhouse, R, Guyonnet, L, Farrah, T, Lenoir, O, Owen, E, van Bragt, J, Costello, H.M., Menolascina, F, Baudrie, V, Webb, D.J., Kluth, D.C., Bailey, M.A., Tharaux, PL & Dhaun, N (2019): A novel role for myeloid endothelin-B receptors in hypertension. European Heart Journal 40 (9), 768-784

Culshaw, G.J., Costello, H.M., Binnie, D, Stewart, K.R., Czopek, A, Dhaun, N, Hadoke, P.W.F., Webb, D.J. & Bailey, M.A. (2019): Impaired Pressure Natriuresis and Non-Dipping Blood Pressure in Rats with Early Type 1 Diabetes Mellitus: Pressure natriuresis and BP in T1DM. Journal of Physiology 597 (3), 767-780

Ivy, J.R., Jones, N.K., Costello, H.M., Mansley, M.K., Peltz, T.S., Flatman, P.W., Bailey, M.A. (2019): Glucocorticoid receptor activation stimulates the Na-Cl co-transporter and influences the diurnal rhythm of its phosphorylation. Am J Physiol Renal Physiol, DOI 10.1152/ajprenal.00372.2019

Ralph, A.F., Grenier C, Costello, H.M., Stewart, K, Ivy, J.R., Dhaun, N, Bailey, M.A. (2021): Activation of the sympathetic nervous system promotes blood pressure salt-sensitivity in C57BL6 mice. Hypertension 77, 158-168.

glucocorticoids

Cushing’s syndrome

salt-sensitive

kidney artery function

spironolactone

stress

Relationship between salt and glucocorticoids: implications for salt-sensitive hypertension

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy