Biology subjects

Mullins, L. J.

Publications and source records attributed to Mullins, L. J..

3 recordsLinked to original sources

bioRxiv2022

Glucocorticoid involvement in reproductive biology

Oestrogen and progesterone play essential roles in the release of mature oocytes, the priming and cycling of the uterine lining, and the maintenance of mammalian pregnancy. Progesterone is synthesized de novo at the embryo implantation site in the mouse, during decidualization of the endometrium. During early stages of pregnancy, the locally produced progesterone is thought to act as an immunosuppressant, preventing rejection of the fetal allograft at the fetal-maternal interface. However, both uterine natural killer cells and dendritic cells express glucocorticoid receptor rather than progesterone receptor. The importance of glucocorticoids in early pregnancy is inferred from the presence of steroid receptors and the 11{beta}-hydroxysteroid dehydrogenase enzymes, which modulate corticosterone action in the decidua, the trophoblast, the placenta, and the fetus. 11{beta}-hydroxylase is the last enzyme in the metabolism of cholesterol to corticosterone and, in a mouse model of 11{beta}-hydroxylase deficiency, complications of reproduction suggested its requirement for normal ovulation and uterine cell turnover. We present evidence that, in this model, folliculogenesis occurs normally but ovulation is inhibited, and abnormal uterine cell turnover ultimately leads to adenomyosis. Ovaries respond to a superovulation protocol by releasing oocytes and forming corpora lutea, and homozygous null blastocysts are capable of implantation, but the pregnancy is not maintained. We show that glucocorticoid is produced locally at the implantation site in control animals, revealing wide involvement of glucocorticoids in reproductive biology.

physiology↗

bioRxiv2022

Late Fetal and Newborn Granulopoiesis but not Active Renin is Increased by Maternal Captopril Treatment During Perinatal Kidney Development

Renin expression follows vascular development through the mouse kidney, regressing to glomerular poles by about P10, where renin is stored in dense core granules in juxtaglomerular cells. Homeostatic challenge to blood pressure causes release of active renin from the granules and recruitment of the renin lineage cells. We investigated the response to homeostatic challenge during late fetal development and following birth in a transgenic line expressing GFP under the renin promotor. Pregnant females were treated with water or captopril (30mg/kg/day), which inhibits angiotensin converting enzyme, from E15.5. We found an increase in renin transcription and expression by P1 following captopril treatment, with granulation increased at the glomerular poles and major arteries from E18.5. At P1, the granules showed a wide variation in electron density. Notably, rough endoplasmic reticulum was expanded in vascular smooth muscle cells (VSMCs) of captopril-treated pups at both time-points suggesting increased transcriptional activity. Paracrystalline material was observed in granules of captopril treated fetuses at E18.5 and in both treated and untreated pups at P1. Renin expression and some granules were confirmed in the kidney VSMCs by immuno-gold staining against GFP at E18.5. Importantly, we found no difference in active renin content between kidneys from treated and untreated pups at either age group. We therefore demonstrate a disconnect between granulation and active renin production in newborns when exposed to homeostatic challenge in utero.

developmental biology↗

bioRxiv2022

Vagal involvement in non-dipping phenotype of Hsd11b2 knockout rats

The Syndrome of Apparent Mineralocorticoid Excess (SAME) is a hypertensive disorder caused by deficiency of 11b-hydroxysteroid dehydrogenase type 2. Blood pressure is directly influenced by dietary salt intake, but the causes of salt-sensitivity are not fully resolved. We modelled SAME in Fischer 344 rats, using zinc finger nuclease targeting of the Hsd11b2 gene. The F344 genetic background showed modest salt sensitivity: blood pressure increased by [~]6mmHg when diet was switched from control (0.3% Na) to high salt (3% Na) diet. Homozygous knockout (Hsd2-/-) rats exhibited severe hypertension on control diet (mean arterial blood pressure of [~]180 mmHg compared to [~]115 mmHg in wild-types) and displayed no dipping in blood pressure in the inactive/sleep phase. They also displayed reduced heart rate (339 bpm versus 384 bpm in F344 controls). Low salt diet (0.03% Na) caused a dramatic fall in Hsd2-/- blood pressure (to [~]141mmHg), restoration of robust circadian variation in blood pressure, and an increase in heart rate (to 364bpm). This was mirrored by a restoration of circadian variation in the Poincare plot descriptor, SD1, suggesting involvement of parasympathetic dysfunction in the non-dipping phenotype. Alpha adrenoceptor blockade with prazosin treatment resulted in a further decrease in blood pressure (to [~]124mmHg), which blunted circadian rhythm, together with an increase in heart rate (to [~]394bpm). This rat model of human hypertension reveals clear links between dietary salt, autonomic nervous system dysfunction, and the non-dipping blood pressure phenotype.

physiology↗