REVIEW the Renin–Angiotensin System in Thyroid Disorders and Its
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25 REVIEW The renin–angiotensin system in thyroid disorders and its role in cardiovascular and renal manifestations Fe´lix Vargas, Isabel Rodrı´guez-Go´mez, Pablo Vargas-Tendero, Eugenio Jimenez1 and Mercedes Montiel1 Departamento de Fisiologı´a, Facultad de Medicina, Universidad de Granada, E-18012 Granada, Spain 1Departamento de Bioquı´mica y Biologı´a Molecular e Inmunologı´a, Facultad de Medicina, Universidad de Ma´laga, Boulevard Louis Pasteur 32, 29071 Ma´laga, Spain (Correspondence should be addressed to F Vargas; Email: [email protected]) Abstract Thyroid disorders are among the most common endocrine while RAS components act systemically and locally in diseases and affect virtually all physiological systems, with an individual organs. Various authors have implicated the especially marked impact on cardiovascular and renal systems. systemic and local RAS in the mediation of functional and This review summarizes the effects of thyroid hormones on structural changes in cardiovascular and renal tissues due to the renin–angiotensin system (RAS) and the participation of abnormal thyroid hormone levels. This review analyzes the the RAS in the cardiovascular and renal manifestations of influence of thyroid hormones on RAS components and thyroid disorders. Thyroid hormones are important regulators discusses the role of the RAS in BP, cardiac mass, vascular of cardiac and renal mass, vascular function, renal sodium function, and renal abnormalities in thyroid disorders. handling, and consequently blood pressure (BP). The RAS Journal of Endocrinology (2012) 213, 25–36 acts globally to control cardiovascular and renal functions, Thyroid hormones and the renin–angiotensin important role in the function of these organs and is involved system in cell growth, angiogenesis, proliferation, among others. The local RAS appears to be regulated independently from the Classically, the renin–angiotensin system (RAS) consists of a circulating system in a specific manner according to the cell cascade of reactions in which angiotensinogen, substrate of type and extracellular stimulus, although it can interact with the RAS, is cleaved by renin released into the circulation to and complement the circulating system. An intracellular RAS generate the decapeptide angiotensin I (AI). The peptidyl- was recently reported, characterized by the presence of a dipeptidase angiotensin-converting enzyme (ACE), a complete functionally active RAS within the cell that can membrane-bound metalloprotease primarily present on synthesize AII in an independent manner (Kumar et al. 2007). endothelial cells, converts AI to the octapeptide angiotensin II Hence, the RAS is a paracrine and intracrine system as well as (AII). AII is the most active known peptide of the RAS and an endocrine system (Fyhrquist & Saijonmaa 2008). acts on various tissues in the body via selective binding to two Recognition of the important role of intracellular RAS in major subtypes of G-protein-coupled receptors: AII type 1 the cardiovascular system has grown over the past few (AT1) and type 2 (AT2) receptors. The role of the RAS in decades, with observations that the heart, vascular smooth blood pressure (BP) control is well documented, but it is also muscle cells (VSMCs), and fibroblasts can intracellularly involved in the local regulation of numerous functions and generate the vasoactive peptide AII. can be influenced by different stimuli and hormones, Thyroid hormones play an important role in BP control including thyroid hormones. but can exert many other effects on the cardiovascular system, The RAS is more complex than originally thought, and both hypo- and hyperthyroidism can cause cardiovascular because it operates not only as a circulating endocrine system dysfunction (Klein & Ojamaa 1995, 2001, Vargas et al. 2006, but also as a local tissue system (Dzau & Herrmann 1982) Ichiki 2010). Thyroid hormones are known to increase the that has been identified in most organs and tissues studied response of tissues to the action of the sympathetic system, (e.g. heart, blood vessels, kidney, adrenal gland, pancreas, and this may be a mechanism by which they regulate BP. CNS, reproductive system, and fatty tissues). It plays an However, thyroid hormones can also activate the RAS Journal of Endocrinology (2012) 213, 25–36 DOI: 10.1530/JOE-11-0349 0022–0795/12/0213–025 q 2012 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 10/01/2021 02:40:11PM via free access 26 F VARGAS and others . Renin–angiotensin system in thyroid disorders without involving the sympathetic nervous system (Kobori have demonstrated the influence of thyroid hormones on et al. 2001). circulating renin. Experimental hyperthyroidism produces an Numerous studies have been performed to characterize the increase in plasma renin activity (PRA) and plasma renin physiological role of thyroid hormones in controlling the concentration (PRC), while the induction of hypothyroidism synthesis and secretion of RAS components (Jime´nez et al. in adult rats reduces PRA and PRC (Hauger-Klevene & 1982, Montiel et al. 1987, Carneiro-Ramos et al. 2006, Diniz Levin 1976, Jime´nez et al. 1982). However, different results et al. 2009). Several in vivo and in vitro studies have reported were obtained when hypothyroidism was induced by surgical that thyroid hormones might modulate the RAS and have thyroidectomy in rats in the first day of life, when an increase evidenced a relationship between the thyroid state and RAS in renal renin content (Bouhnik et al. 1981) and PRC components at both plasma and tissue levels (Kumar et al. (Jime´nez et al. 1984) was observed, suggesting the operation 2008, Barreto-Chaves et al. 2010). Thyroid hormones play a of distinct mechanisms according to the age at which the major role in the growth and development of various tissues, thyroid hormone deficit is produced. including the kidney and lung, which are major sites of renin In vitro studies indicated that thyroid hormones influence and ACE synthesis; therefore, thyroid hormone deficiency in the synthesis and secretion of renin by juxtaglomerular early developmental stages can have significant effects on RAS cells. Ichihara et al. (1998) found that triiodothyronine (T3) components (Chen et al. 2005). In this study, we review the administration increases renin secretion, renin content, and effects of a deficit or excess of thyroid hormones on RAS renin mRNA in rat juxtaglomerular cell cultures. Various components (Table 1). authors observed this direct action in cardiac tissue from hyperthyroid rats and reported that thyroid hormones directly stimulate renin mRNA and the promoter activity of the Renin human renin gene via thyroid hormone regulating element- Since the discovery of renin 100 years ago, various tissues have dependent mechanisms (Gilbert et al. 1994, Kobori et al. been found to express the renin gene, although the main 1997a,b, 2001). These actions of thyroid hormones on renin source of circulating renin production is located in secretion and renin mRNA are direct and not mediated by juxtaglomerular kidney cells (Kurtz 2011). Renin is an changes in sympathetic nervous system activity (Kobori et al. aspartyl protease that cleaves AI decapeptide from the 1997a,b). However, the above studies do not rule out the angiotensinogen molecule, and numerous in vivo studies possibility that RAS activity modifications in thyroid Table 1 Plasma and local renin–angiotensin compounds in thyroid hormone excess or deficit Compound Hyperthyroidism Hypothyroidism Plasma Angiotensinogen [ (Dzau & Herrmann 1982, Marchant et al. 1993); Y (Bouhnik et al. 1981, Jime´nez et al. 1982, Y (Jime´nez et al. 1982) Katz 2003) Renin [ (Hauger-Klevene & Levin 1976, Jime´nez et al. [ (Jime´nez et al. 1984); Y (Hauger-Klevene & 1982, Santos & Ferreira 2007) Levin 1976, Jime´nez et al. 1982) Angiotensin-converting enzyme [ (Phillips et al. 1993) Y (Montiel et al. 1987, Jime´nez et al. 1990) Angiotensin II [ (Marchant et al. 1993, Garcia del Rı´o et al. Y (Marchant et al. 1993, Kobori et al. 1997a,b) 1997, Kobori et al. 1997a,b) New RAS components – – Heart Renin [ (Kobori et al. 1997a,b)– Angiotensin II [ (Kobori et al. 1997a,b, 1999, Diniz et al. 2007) Z (Carneiro-Ramos et al. 2007) / Y Z [ AT1R (Carneiro-Ramos et al. 2010); (Marchant (Marchant et al. 1993); (Carneiro-Ramos et al. 1993) et al. 2007) [ [ AT2R (Marchant et al. 1993, Carneiro-Ramos (Marchant et al. 1993, Carneiro-Ramos et al. 2010) et al. 2007) Kidney Renin [ (Bouhnik et al. 1981, Kobori et al. 1997a,b, Y (Kobori et al. 1997a,b) Klein & Ojamaa 2001) Angiotensin II [ (Klein & Ojamaa 2001)– Y AT1R– (Chen et al. 2005) [ AT2R– (Chen et al. 2005) Vessels Renin – – Angiotensin II – – Y AT1R (Fukuyama et al. 2003)– [ AT2R (Barreto-Chaves et al. 2010)– F, Forward; R, reverse. Journal of Endocrinology (2012) 213, 25–36 www.endocrinology-journals.org Downloaded from Bioscientifica.com at 10/01/2021 02:40:11PM via free access Renin–angiotensin system in thyroid disorders . F VARGAS and others 27 disorders in vivo may be in part mediated by changes in ACE activity is influenced by thyroid dysfunction at b-adrenergic activity. In fact, an increased number of both circulating and tissue levels. Reduced serum and liver b-adrenergic receptors were found in the renal cortex in ACE concentrations were reported in neonatal rats with experimental hyperthyroidism (Haro et al. 1992), and PRA is hypothyroidism induced by maternal administration of enhanced by b-adrenergic