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ABSTRACT
The influence of thyroid hormones on angiotensinogen production was studied in vitro and in vivo. In the in-vitro system, angiotensinogen production rate (APR) of monolayer cultures of rat hepatocytes in response to tri-iodothyronine (T3) and thyroxine (T4) was assayed. In the in-vivo system, plasma angiotensinogen concentration (PAC) and liver angiotensinogen content (LAC) were measured in hyper- and hypothyroid rats. In both thyroid dysfunctions, a significant decrease of PAC was found compared with that in control animals; however, LAC showed a significant increase in hyperthyroidism and a marked decrease in hypothyroidism. As PAC is dependent upon both angiotensinogen production by the liver and angiotensinogen degradation by renin, the decrease in PAC observed in hyperthyroidism could be due to an increase in plasma renin concentration, which would overcome the increased synthesis of liver angiotensinogen observed in these animals. In fact, addition of various concentrations of T4 or T3 to monolayer cultures of adult rat hepatocytes significantly enhanced APR. This increase was greater and started earlier with T3 (1196·1 ± 143·7 (s.d.) pg/mg protein per 6-h incubation; significant differences at the third hour of incubation) than with T4 (858·3 ± 88·2 pg/mg protein per 6-h incubation; significant differences at the sixth hour of incubation). In addition, a close dose–response relationship was found in the cultures supplemented with T3. The different time-course in the response elicited by T3 and T4 on APR could be a consequence of the necessary transformation of T4 into T3 to acquire biological activity.
J. Endocr. (1987) 115, 311–315
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Abstract
In order to obtain more information on the molecular structure of the angiotensin II (Ang II) binding sites from whole rat lung membranes these were characterized by isoelectric focusing (IEF) and SDS-PAGE. Whereas a single population of Ang II receptor sites was identified (K d=2·2± 0·3 nmol/l; Bmax=203·9± 15·8 fmol/mg protein) by Scatchard analysis, using IEF three Ang II binding isoforms were observed; a major band which migrated to isoelectric point (pI) 6·7, and two minor bands with pI values of 6·5 and 6·3 Specific binding of 125I-Ang II to rat lung membrane preparations was sensitive to Losartan, a non-peptide AT1, receptor subtype antagonist, but was unaffected by the AT2 receptor subtype antagonist CGP42112A. Immunoblotting analyses on SDS gels, using a monoclonal antibody specific to the AT1, receptor, showed two immunoreactive protein species of 45 and 48 kDa. Enzymic deglycosylation using recombinant N-glycanase did not alter the molecular weight patterns of the AT1, receptor subtype. The results of the present study demonstrated that the Ang II receptor population in the whole rat lung consists solely of the AT1, receptor subtype and that the AT2 receptor subtype is absent. In addition, the data showed the existence of charge heterogeneity of the AT1, receptor subtype, and suggest that glycosylation probably does not contribute to its charge heterogeneity.
Journal of Endocrinology (1995) 147, 153–159
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ABSTRACT
Plasma angiotensin II (AII) concentration, plasma renin concentration (PRC), lung angiotensin-converting enzyme (ACE) activity and adrenal gland AII receptor isoforms have been evaluated in the postnatal development of the rat, in order to determine the alterations of the renin-angiotensin system (RAS) which occur in congenital hypothyroidism. The developmental AII profiles observed in control and hypothyroid rats were quite similar. Thus, AII was elevated at birth and declined at week 5 of life to reach adult values. However, AII levels were lower in hypothyroid than in euthyroid animals before their stabilization. On the other hand, PRC in newborn hypothyroid and euthyroid animals was higher than in adulthood, being significantly increased immediately after birth in hypothyroid rats. Pulmonary ACE activity in both experimental groups was low at birth and increased with age. This increase was greater in euthyroid rats than in congenitally hypothyroid animals from day 28 of life. These results confirm that plasma AII levels in rats are predominantly controlled by plasma renin activity, although other factors, such as renin substrate availability, may be responsible for the reduced plasma AII concentration in congenital hypothyroidism during the first weeks of life.
The developmental profile of the adrenal gland AII receptor showed four isoforms, with pI values of 6·8, 6·7, 6·5 and 6·3. AII receptor-complex expression increased with age but, in congenitally hypothyroid rats, a higher induction of AII receptor isoforms migrating to pI 6·8, 6·5 and 6·3 was observed.
These findings show that thyroid hormone deficiency in early life can have an important role in the postnatal induction of the RAS components, which may be essential for the regulation of blood pressure, and for fluid and electrolyte balance in developing rats.
Journal of Endocrinology (1993) 137, 231–238
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Angiotensin II (Ang II) provokes rapid internalisation of its receptor from plasma membranes in isolated rat hepatocytes. After 10 min stimulation with Ang II, plasma membrane lost about 60% of its 125I-Ang II-binding capacity. Internalisation was blocked by phenylarsine oxide (PhAsO), whereas okadaic acid, which markedly reduced the sustained phase of calcium mobilization, did not have a preventive effect on Ang II–receptor complex sequestration. These data suggest that Ang II receptor internalisation is probably independent of a phosphorylation/dephosphorylation cycle of critical serine/threonine residues in the receptor molecule. To establish a relationship between sequestration of the Ang II receptor and the physical properties of the Ang II-binding sites, 125I-Ang II–receptor complex profiles were analysed by isoelectric focusing. In plasma membrane preparations two predominant Ang II-binding sites, migrating to pI 6·8 and 6·5 were found. After exposure to Ang II, cells lost 125I-Ang II-binding capacity to the Ang II–receptor complex migrating at pI 6·8 which was prevented in PhAsO-treated cells. Pretreatment of hepatocytes with okadaic acid did not modify Ang II–receptor complex profiles, indicating that the binding sites corresponding to pI 6·5 and pI 6·8 do not represent a phosphorylated and/or non-phosphorylated form of the Ang II receptor. The results show that the Ang II–receptor complex isoform at pI 6·8 represents a functional form of the type-1 Ang II receptor. Further studies are necessary to identify the Ang II-related nature of the binding sites corresponding to pI 6·5.
Journal of Endocrinology (1997) 152, 407–412
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Abstract
Isoelectric focusing analysis showed a single angiotensin II (All)-receptor complex migrating to pI 6·8 in nuclear preparations, while in plasma membranes a charge heterogeneity of the All receptor subtype AT1 was observed. 125I-Labelled All binding sites were found in intact nuclei and were not detected in nuclear extracts. Neither disruption of cytoskeletal elements by colchicine nor prevention of endosome acidification by chloroquine had any effect on nuclear accumulation of AIL Nevertheless, the monovalent ionophore monensin inhibited nuclear accumulation of 125I-Labelled All. Our findings are consistent with the hypothesis that processing through the Golgi apparatus could be involved in the nuclear accumulation of AIL
Journal of Endocrinology (1994) 143, 449–453
