RT Journal Article
SR Electronic
T1 Renal arterial dysfunction, impaired pressure natriuresis and salt-sensitivity in a mouse model of Cushing syndrome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.12.11.625204
DO 10.1101/2024.12.11.625204
A1 Costello, Hannah M
A1 Grenier, Céline
A1 Ivy, Jessica R
A1 Jones, Natalie K.
A1 Stewart, Kevin
A1 Holmes, Megan C
A1 Livingstone, Dawn E.W.
A1 Dhaun, Neeraj
A1 Bailey, Matthew A
YR 2024
UL http://biorxiv.org/content/early/2024/12/11/2024.12.11.625204.abstract
AB Background Cushing Syndrome arises from endogenous overproduction of ACTH by a tumour or is acquired through chronic exposure to glucocorticoid medication. Hypertension is a major complication, increasing cardiovascular risk, but underlying mechanisms are not clearly defined.Methods We infused male C57BL/6J mice with ACTH or vehicle for 14-21 days, inducing cardinal features of Cushing Syndrome. The renal pressure natriuresis response was measured under anesthesia and ex vivo artery function assessed by myography.Results ACTH infusion blunted the natriuretic and diuretic responses to incremental increases in blood pressure. Renal hemodynamics did not change with blood pressure in controls, but renal autoregulation was impaired in ACTH mice. The ex vivo contractile response of the renal artery to phenylephrine was diminished in Cushing Syndrome mice, as was endothelium-dependent and endothelium-independent relaxation. On 0.3% sodium diet, there was no evidence of sodium retention in ACTH-treated mice but the diurnal rhythm of sodium excretion was abnormal and mice had non-dipping BP. The Cushing Syndrome model also displayed enhanced salt preference and amplified salt-sensitive blood pressure.Conclusion Cushing Syndrome induces a cluster of phenotypes impacting sodium homeostasis and blood pressure regulation. Hypertension, salt-sensitivity and non-dipping blood pressure are important cardiovascular risk factors, and, beyond Cushing Syndrome, our findings are relevant to obesity and the metabolic syndrome, in which tissue glucocorticoid homeostasis is abnormal.Competing Interest StatementThe authors have declared no competing interest.