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.

Maternal Dexamethasone Treatment Alters Tissue and Circulating Components of the Renin-Angiotensin System in the Pregnant Ewe and Fetus

“…Significant associations were observed between circulating concentrations of T 3 in the fetus and plasma and pulmonary ACE concentrations, and the transcript levels of ACE in the fetal lungs, kidneys, and heart. These findings support the suggestion that T 3 may have an important role in mediating the regulatory effects of glucocorticoids on tissue and circulating ACE expression in utero ( 46 ). Indeed, in fetal sheep, experimental thyroid hormone deficiency prevents the normal developmental rise in pulmonary and renal ACE concentration near term, and exogenous T 3 infusion has been shown to increase ACE concentration in the fetal lungs, but not kidneys ( 46 ).…”

“…These findings support the suggestion that T 3 may have an important role in mediating the regulatory effects of glucocorticoids on tissue and circulating ACE expression in utero ( 46 ). Indeed, in fetal sheep, experimental thyroid hormone deficiency prevents the normal developmental rise in pulmonary and renal ACE concentration near term, and exogenous T 3 infusion has been shown to increase ACE concentration in the fetal lungs, but not kidneys ( 46 ). Previous studies, however, have shown that maternal dexamethasone treatment has differential effects on the thyroid hormone axis in the pregnant ewe and fetus ( 12 ).…”

Maternal Dexamethasone Treatment Alters Tissue and Circulating Components of the Renin-Angiotensin System in the Pregnant Ewe and Fetus

“…Significant associations were observed between circulating concentrations of T 3 in the fetus and plasma and pulmonary ACE concentrations, and the transcript levels of ACE in the fetal lungs, kidneys, and heart. These findings support the suggestion that T 3 may have an important role in mediating the regulatory effects of glucocorticoids on tissue and circulating ACE expression in utero ( 46 ). Indeed, in fetal sheep, experimental thyroid hormone deficiency prevents the normal developmental rise in pulmonary and renal ACE concentration near term, and exogenous T 3 infusion has been shown to increase ACE concentration in the fetal lungs, but not kidneys ( 46 ).…”

“…These findings support the suggestion that T 3 may have an important role in mediating the regulatory effects of glucocorticoids on tissue and circulating ACE expression in utero ( 46 ). Indeed, in fetal sheep, experimental thyroid hormone deficiency prevents the normal developmental rise in pulmonary and renal ACE concentration near term, and exogenous T 3 infusion has been shown to increase ACE concentration in the fetal lungs, but not kidneys ( 46 ). Previous studies, however, have shown that maternal dexamethasone treatment has differential effects on the thyroid hormone axis in the pregnant ewe and fetus ( 12 ).…”

Gestational age and fetal hypothyroidism Alter the porcine thyroid and local hepatic and renal renin‐angiotensin systems

“…However, a number of prior studies examining the consequences of fetal hypothyroidism on the RAS have suggested a suppression, rather than activation, of the canonical RAS. This is marked by decreased fetal renal REN expression (Chen et al., 2005 ), temporally decreased fetal pulmonary and renal ACE levels (Forhead & Fowden, 2002 ), and decreased postnatal ANGII concentrations following congenital hypothyroidism (Matilla et al., 1993 ). Additionally, hypothyroidism in fetal sheep is known to cause a reduction in blood pressure (Chen et al., 2005 ), indicating fetal hypotension, rather than hypertension.…”

Exploring thyroid function in main domestic ruminants: a scoping review of physio-anatomy, diseases and diagnostic tools

“…Hypothyroidism is implicated in acute respiratory distress syndrome in neonates. Without thyroid hormones, angiotensin is lower at the end of gestation (Forhead and Fowden 2002 ). Thyroid hormones play an important role in controlling lung and kidney development (Liggins et al.…”

“… 1988 ; Schellenberg et al. 1988 ; Forhead and Fowden 2002 ), especially T4 in lung maturation and surfactant production, together with cortisol (Jones et al. 1986 ).…”

Maternal Dexamethasone Treatment Alters Tissue and Circulating Components of the Renin-Angiotensin System in the Pregnant Ewe and Fetus

“…Significant associations were observed between circulating concentrations of T 3 in the fetus and plasma and pulmonary ACE concentrations, and the transcript levels of ACE in the fetal lungs, kidneys, and heart. These findings support the suggestion that T 3 may have an important role in mediating the regulatory effects of glucocorticoids on tissue and circulating ACE expression in utero ( 46 ). Indeed, in fetal sheep, experimental thyroid hormone deficiency prevents the normal developmental rise in pulmonary and renal ACE concentration near term, and exogenous T 3 infusion has been shown to increase ACE concentration in the fetal lungs, but not kidneys ( 46 ).…”

“…These findings support the suggestion that T 3 may have an important role in mediating the regulatory effects of glucocorticoids on tissue and circulating ACE expression in utero ( 46 ). Indeed, in fetal sheep, experimental thyroid hormone deficiency prevents the normal developmental rise in pulmonary and renal ACE concentration near term, and exogenous T 3 infusion has been shown to increase ACE concentration in the fetal lungs, but not kidneys ( 46 ). Previous studies, however, have shown that maternal dexamethasone treatment has differential effects on the thyroid hormone axis in the pregnant ewe and fetus ( 12 ).…”

Gestational age and fetal hypothyroidism Alter the porcine thyroid and local hepatic and renal renin‐angiotensin systems

“…However, a number of prior studies examining the consequences of fetal hypothyroidism on the RAS have suggested a suppression, rather than activation, of the canonical RAS. This is marked by decreased fetal renal REN expression (Chen et al., 2005 ), temporally decreased fetal pulmonary and renal ACE levels (Forhead & Fowden, 2002 ), and decreased postnatal ANGII concentrations following congenital hypothyroidism (Matilla et al., 1993 ). Additionally, hypothyroidism in fetal sheep is known to cause a reduction in blood pressure (Chen et al., 2005 ), indicating fetal hypotension, rather than hypertension.…”

Exploring thyroid function in main domestic ruminants: a scoping review of physio-anatomy, diseases and diagnostic tools

“…Hypothyroidism is implicated in acute respiratory distress syndrome in neonates. Without thyroid hormones, angiotensin is lower at the end of gestation (Forhead and Fowden 2002 ). Thyroid hormones play an important role in controlling lung and kidney development (Liggins et al.…”

“… 1988 ; Schellenberg et al. 1988 ; Forhead and Fowden 2002 ), especially T4 in lung maturation and surfactant production, together with cortisol (Jones et al. 1986 ).…”

Maternal Dexamethasone Treatment Alters Tissue and Circulating Components of the Renin-Angiotensin System in the Pregnant Ewe and Fetus

“…Significant associations were observed between circulating concentrations of T 3 in the fetus and plasma and pulmonary ACE concentrations, and the transcript levels of ACE in the fetal lungs, kidneys, and heart. These findings support the suggestion that T 3 may have an important role in mediating the regulatory effects of glucocorticoids on tissue and circulating ACE expression in utero ( 46 ). Indeed, in fetal sheep, experimental thyroid hormone deficiency prevents the normal developmental rise in pulmonary and renal ACE concentration near term, and exogenous T 3 infusion has been shown to increase ACE concentration in the fetal lungs, but not kidneys ( 46 ).…”

“…These findings support the suggestion that T 3 may have an important role in mediating the regulatory effects of glucocorticoids on tissue and circulating ACE expression in utero ( 46 ). Indeed, in fetal sheep, experimental thyroid hormone deficiency prevents the normal developmental rise in pulmonary and renal ACE concentration near term, and exogenous T 3 infusion has been shown to increase ACE concentration in the fetal lungs, but not kidneys ( 46 ). Previous studies, however, have shown that maternal dexamethasone treatment has differential effects on the thyroid hormone axis in the pregnant ewe and fetus ( 12 ).…”

Gestational age and fetal hypothyroidism Alter the porcine thyroid and local hepatic and renal renin‐angiotensin systems

“…However, a number of prior studies examining the consequences of fetal hypothyroidism on the RAS have suggested a suppression, rather than activation, of the canonical RAS. This is marked by decreased fetal renal REN expression (Chen et al., 2005 ), temporally decreased fetal pulmonary and renal ACE levels (Forhead & Fowden, 2002 ), and decreased postnatal ANGII concentrations following congenital hypothyroidism (Matilla et al., 1993 ). Additionally, hypothyroidism in fetal sheep is known to cause a reduction in blood pressure (Chen et al., 2005 ), indicating fetal hypotension, rather than hypertension.…”

Exploring thyroid function in main domestic ruminants: a scoping review of physio-anatomy, diseases and diagnostic tools

“…Hypothyroidism is implicated in acute respiratory distress syndrome in neonates. Without thyroid hormones, angiotensin is lower at the end of gestation (Forhead and Fowden 2002 ). Thyroid hormones play an important role in controlling lung and kidney development (Liggins et al.…”

“… 1988 ; Schellenberg et al. 1988 ; Forhead and Fowden 2002 ), especially T4 in lung maturation and surfactant production, together with cortisol (Jones et al. 1986 ).…”