Effects of thyroid hormones on pulmonary and renal angiotensin-converting enzyme concentrations in fetal sheep near term

Abstract

In the sheep fetus, pulmonary and renal concentrations of angiotensin-converting enzyme (ACE) increase towards term in parallel with the prepartum surges in plasma cortisol and tri-iodothyronine (T 3 ). The ontogenic change in pulmonary ACE has been shown to be induced, at least in part, by cortisol but the role of the thyroid hormones is unknown. Therefore, this study investigated the effects of thyroid hormones on tissue ACE concentration in fetal sheep during late gestation. Pulmonary and renal ACE concentrations were measured in sheep fetuses after experimental manipulation of thyroid hormone status by fetal thyroidectomy and exogenous hormone infusion. In intact fetuses, pulmonary and renal ACE concentrations increased between 127-132 and 142-145 days of gestation (term 145 2 days), coincident with the prepartum rises in plasma cortisol and T 3 . The ontogenic increment in pulmonary ACE concentration was abolished when the prepartum surge in T 3 , but not cortisol, was prevented by fetal thyroidectomy. At 143-145 days, ACE concentration in the lungs and kidneys of the thyroidectomised fetuses were both lower than those in the intact fetuses. In intact fetuses at 127-132 days, pulmonary ACE was upregulated by intravenous infusions of either cortisol (2-3 mg/kg per day) or T 3 (8-12 µg/kg per day) for 5 days. Renal ACE was unaffected by cortisol or T 3 infusion. Therefore, thyroid hormones have an important role in the developmental control of pulmonary and renal ACE concentration in the sheep fetus towards term. In addition, the prepartum rise in plasma T 3 appears to mediate, in part, the maturational effect of cortisol on pulmonary ACE concentration.

Thyroid hormone modulates renin and ANG II receptor expression in fetal sheep

“…This is most likely due, in part, to the lack of thyroid hormone stimulation of lung ACE activity, which, in turn, usually facilitates RAS development in preparation for postnatal life (62). TX is associated with significantly decreased lung ACE concentrations in the fetal sheep (18). ANG II, through the AT1 receptor, also is believed to play an important role in fetal lung development and maturation.…”

“…Changes in expression of the levels of ANG II receptor subtypes 1 and 2 (AT1 and AT2) are opposite, with AT1 mRNA low in early gestation and rising to a plateau later, before increasing rapidly close to term, whereas AT2 expression is highest during midpregnancy and then decreases gradually thereafter (46, 47). Tissue-dependent differences also are apparent (18,40,66). The mechanisms underlying these ontogenic patterns of expression are not clear.…”

Hormones as epigenetic signals in developmental programming

“…In part, these effects of glucocorticoids on tissue IGF‐I and IGF‐II synthesis are mediated via the thyroid hormones and the glucocorticoid‐induced changes in tissue deiodinase activity (Forhead et al 2002 a , b , 2006, 2007). Thyroid hormones also modify the effects of glucocorticoids on gluconeogenic enzyme activities in the liver and angiotensin‐converting enzyme activity in the lungs and kidneys of fetal sheep (Fowden et al 2001; Forhead & Fowden, 2002). In addition, glucocorticoids alter the secretion and/or bioactivity of leptin, adrenomedullary hormones, the renin–angiotensin system and pancreatic hormones, either by effects on development of the endocrine cells or by changes in receptor abundance in the target tissues (Blondeau et al 2001; Forhead et al 2002 a ; Moritz et al 2002; O'Connor et al .…”

Thyroid hormone drives fetal cardiomyocyte maturation

“…Thus, total T 3 levels increase from ~0.3 to ~1.5 nM in fetal sheep during the last weeks before delivery (8). This prepartum rise in T 3 promotes maturational processes in lung, liver, and kidney (11–13), and presumably in other organs as well.…”