The renin-angiotensin system in thyroid disorders and its role in cardiovascular and renal manifestations

Thyroid disorders are among the most common endocrine diseases and affect virtually all physiological systems, with an especially marked impact on cardiovascular and renal systems. This review summarizes the effects of thyroid hormones on the renin-angiotensin system (RAS) and the participation of the RAS in the cardiovascular and renal manifestations of thyroid disorders. Thyroid hormones are important regulators of cardiac and renal mass, vascular function, renal sodium handling, and consequently blood pressure (BP). The RAS acts globally to control cardiovascular and renal functions, while RAS components act systemically and locally in individual organs. Various authors have implicated the systemic and local RAS in the mediation of functional and structural changes in cardiovascular and renal tissues due to abnormal thyroid hormone levels. This review analyzes the influence of thyroid hormones on RAS components and discusses the role of the RAS in BP, cardiac mass, vascular function, and renal abnormalities in thyroid disorders.     

The role of the renin-angiotensin system in aortic aneurysmal diseases

The renin-angiotensin system has been invoked in the development of both abdominal and thoracic aortic aneurysms. This has been demonstrated experimentally by the chronic subcutaneous infusion of angiotensin II, which consistently leads to development of abdominal aortic aneurysms (AAAs) in mice. Angiotensin II-induced AAAs have highly heterogenous cellular and extracellular matrix characteristics throughout the aorta that change markedly with infusion duration. The mechanistic basis for the reproducible location of AAA development has not been elucidated, but many insights have been provided, especially regarding receptor and inflammatory mechanisms. A recent clinical study provided limited evidence for extrapolating these results to mechanisms of human AAAs. Experimental evidence has also demonstrated that antagonism of angiotensin II type 1 (AT1) receptors prevents ascending aortic aneurysms in a murine model of Marfan’s syndrome. A clinical study is currently ongoing to demonstrate the efficacy of AT1 receptor antagonism in humans.     

Polymorphism of the renin-angiotensin system and renal failure

The renin-angiotenin-aldosterone system (RAAS) is not only involved in cardiovascular disease but also in renal pathophysiology and progression of renal disease. Several polymorphisms of genes coding for components of the RAAS have been identified. The I/D polymorphism of the ACE gene, a variant of the angiotensiogen gen, the M235T polymorphism, and the variant A1166 C polymorphism of the angiotensin II type 1 receptor gene are the most important. Several studies have suggested a potential role for I/D polymorphism of the ACE gen in the progression of renal diseases and in the cardiovascular death rate of patients with renal failure. Data on RAAS polymorphisms as determinants of the prevalence of renal diseases and the response to renoprotective therapies are conflicting. Given the polygenic nature of renal and cardiovascular disease and the growing number of candidate genes, large prospective and collaborative studies are required to assess the effect of RAAS polymorphisms on the progression of renal disease and on the response to renoprotective therapies.     

The biochemistry of the renin-angiotensin system and its role in hypertension.

The renin-angiotensin system has an important role in maintaining elevated blood pressure levels in certain forms of experimental and human hypertension. Renin, an enzyme produced by the juxtaglomerular cells of the kidney, acts on a protein substrate found in the alpha 2-globulin fraction of the plasma to produce a decapeptide, angiotensin I. This decapeptide is not directly pressor, but on passage through the pulmonary circulation is converted to an octapeptide, angiotensin II, a very potent pressor substance which acts by causing constriction of arteriolar smooth muscle. In addition to its direct action which increases blood pressure, angiotensin II acts on the adrenal cortex to cause the release of the sodium-retaining hormone aldosterone. Recent evidence suggests that this action may be mediated by the heptapeptide, angiotensin III. Both renin and its protein substrate exist in multiple forms and renin may also exist as a high molecular-weight "pro-hormone," although the physiologic significance of these forms is not clear. The elucidation of the biochemistry of the renin-angiotensin system has provided us with inhibitors which allow the system to be blocked effectively in vivo. Thus, angiotensin antagonists such as Sar 1, IIe 8-angiotensin II and converting enzyme inhibitors such as BPP 9a (SQ 20881) have proved useful in the study of experimental and human hypertension.     

Blockade of the renin-angiotensin and endothelin systems on progressive renal injury

The renin-angiotensin system (RAS) and endothelin system may both play a role in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockade of the RAS with an ACE inhibitor and an angiotensin type 1(AT1) receptor antagonist; second, to examine the relative efficacy of endothelin A receptor antagonism (ETA-RA) compared with combined endothelin A/B receptor antagonism (ETA/B-RA); and third, to assess whether interruption of both RAS and endothelin system had any advantages over single-system blockade. Subtotally nephrectomized rats were studied as a model of progressive renal injury and randomly assigned to one of the following treatments for 12 weeks: perindopril (ACE inhibitor), irbesartan (AT1 receptor antagonist), BMS193884 (ETA-RA), bosentan (ETA/B-RA), and a combination of irbesartan with either perindopril or BMS193884. Treatment with irbesartan or perindopril was associated with an improved glomerular filtration rate and reductions in blood pressure, urinary protein excretion, glomerulosclerosis, and tubular injury in association with reduced gene expression of transforming growth factor-beta(1) and matrix protein type IV collagen. The combination of irbesartan with perindopril was associated with further reductions in blood pressure and urinary protein excretion. No beneficial effects of either BMS193884 or bosentan were noted. Furthermore, the addition of BMS193884 to irbesartan did not confer any additional benefits. These findings suggest that the RAS but not the endothelin system is a major mediator of progressive renal injury after renal mass reduction and that the combination of an AT1 receptor antagonist with an ACE inhibitor may have advantages over the single agent of RAS blocker treatment.     

The role of nitric oxide and the renin-angiotensin system in salt-restricted Dahl rats

To elucidate the role of nitric oxide (NO) and renin-angiotensin system (RAS) in the development of salt-sensitive hypertension, we investigated the pressor responses and renal histologic changes after long-term inhibition of endogenous NO synthesis in Dahl-Iwai salt-sensitive (DS) and salt-resistant (DR) rats under salt-re-stricted conditions that exaggerate RAS activation. Male DS and DR rats (6 weeks old) were fed with a low-salt (0.3%) diet for 5 weeks. NG-nitro-L-arginine (L-NA; dissolved in 60 mg/L deionized water), an arginine analogue acting as a NO-inhibitor, was also administered for 5 weeks. L-NA administration induced a gradual increase in systolic blood pressure (SBP) in both strains, and the pressor response in DS rats was apparently more enhanced relative to that in DR rats. Urinary nitrate plus nitrite (u-NOx) excretion was decreased by L-NA, with a significant negative correlation between SBP and u-NOx excretion in DS rats but not in DR rats. Plasma renin activity and urinary aldosterone level were significantly increased in L-NA-treated DS rats on week 5. Marked histologic changes with glomerular sclerosis and increased proteinuria and urinary N-acetyl-beta-glucosaminidase excretion were found in L-NA-treated DS rats but not DR rats. Competitive RT-PCR of mRNA extracted from the glomeruli revealed that angiotensin II type 1 receptor (AT1R) mRNA level was significantly lower in DS rats than in DR rats at week 2, and that L-NA administration significantly reduced glomerular AT1R level of DS rats at week 5, possibly because of downregulation. Our results showed that, even under sodium restriction, the pressor response and renal injury induced by chronic NO inhibition were markedly more enhanced in DS rats than in DR rats, which indicates that depletion of NO participates in both the development of hypertension and glomerular injury in DS rats through a potential activation of RAS irrespective of sodium loading. These data suggest that endogenous NO is an essential determinant of salt-sensitive hypertension in DS rats.     

The renin-angiotensin system and its blockade in diabetic renal and cardiovascular disease

Diabetic nephropathy, the most common cause of end-stage renal disease in the United States, is also associated with increased cardiovascular mortality. The renin-angiotensin-aldosterone system (RAAS) plays a central role in the development and progression of kidney disease and cardiovascular disease. Randomized, controlled trials have demonstrated renoprotection with the use of angiotensin receptor blockers (ARBs) in type 2 and angiotensin-converting enzyme inhibitors (ACEIs) in type 1 diabetes. More recent studies have demonstrated similar cardiovascular bene.ts with the use of ARBs compared with ACEIs. The combination of the two classes of RAAS blockers has been investigated in large studies of patients with heart failure and after myocardial infarction, and a few small studies of patients with diabetic nephropathy. In this review, we summarized the results of the studies on the benefits of ARBs, ACEIs, and their combination in patients with diabetic nephropathy or cardiovascular diseases.     

Developmental programming of renal glucocorticoid sensitivity and the renin-angiotensin system

Fetal glucocorticoid excess leads to subsequent adult hypertension, but the mechanisms involved in this developmental programming remain largely unknown. In this study we tested the hypothesis that programmed hypertension in rats is linked to altered renal expression of the glucocorticoid receptor, mineralocorticoid receptor, and 11beta-hydroxysteroid dehydrogenase type 2 and components of the intrarenal and adipose renin-angiotensin system. The interactive effects of a postnatal diet enriched in omega-3 fatty acids, which prevents emergence of the hypertensive phenotype, were also examined. Maternal dexamethasone (0.75 microg/mL of drinking water from day 13 to term) markedly increased renal expression of the glucocorticoid receptor in 6-month-old offspring, and this was associated with hypomethylation of the glucocorticoid receptor promoter; renal MR was unaffected. In contrast, maternal dexamethasone reduced renal 11beta-hydroxysteroid dehydrogenase type 2 in offspring, but this effect was prevented by a high omega-3 diet. Consistent with these effects, renal Na/K-ATPase-alpha1 was elevated in offspring of dexamethasone-treated mothers, but only in those raised on the standard diet. Maternal dexamethasone also programmed increased expression of renal and adipose angiotensin-converting enzyme and renal renin, but among these changes, only that of renal angiotensin-converting enzyme was prevented by the omega-3 diet. Our data support the hypothesis that programmed hypertension is mediated, in part, by increased renal glucocorticoid sensitivity, with consequent stimulatory effects on Na/K-ATPase-alpha1 and intrarenal renin-angiotensin system components. Partial prevention of programmed changes in renal gene expression by postnatal dietary omega-3 fatty acids provides insight into how this intervention prevents hypertension induced by fetal glucocorticoid excess.     

New insights into the renin-angiotensin system and hypertensive renal disease

The role of the renin-angiotensin system in hypertension and end organ damage has long been recognized. Recent advances in genetic models and newly available pharmacologic tools have allowed dissection of the mechanisms of actions of the renin-angiotensin system in hypertensive kidney disease. The newly cloned AT2 receptor is now recognized to oppose many of the AT1 receptor’s actions. The renin-angiotensin system is now recognized to be linked to induction of plasminogen activator inhibitor-1 (PAI-1), possibly via the AT4 receptor, thus promoting both thrombosis and fibrosis. Interactions of the reninangiotensin system with aldosterone and bradykinin may have impact on both blood pressure and tissue injury. The effects of angiotensin 1 converting enzyme inhibitors versus those of the newly available AT1 receptor antagonists on blood pressure and organ damage are undergoing evaluation in clinical trials. Finally, polymorphisms of genes relevant to the renin-angiotensin system appear to affect response to treatment, although this effect varies in different populations.     

Hypertension and diabetes: role of the renin-angiotensin system.

Hypertension is often associated clinically with diabetes as part of the insulin-resistance syndrome or as a manifestation of renal disease. Elevated systemic blood pressure accelerates micro- and macrovascular complications in diabetes. Vasoactive hormone pathways including the renin-angiotensin-aldosterone system (RAAS) appear to play a pivotal role in the pathogenesis and progression of diabetic complications and possible diabetes itself. Recent studies have increased our understanding of the complexity of the RAAS with identification of new components of this cascade including angiotensin-converting enzyme 2 and a putative renin receptor. Agents that interrupt the RAAS confer end-organ protection in diabetes via hemodynamic and non-hemodynamic mechanisms. Trials are investigating the possible role of RAAS blockade in the prevention of type 2 diabetes.     

Uric acid: Its relationship to renal hemodynamics and the renal renin-angiotensin system

Reports relating hyperuricemia and hypertension have been fieled for many decades. Nevertheless, controversy remains concerning serum uric acid concentration as an independent risk factor underlying coronary heart disease (CHD) and essential hypertension or as an indirect marker of renovascular involvement. Earlier studies in normotensive subjects and hypertensive patients demonstrated that serum uric acid concentration was closely related to intrarenal hemodynamic alterations, suggesting that it is an excellent marker of vascular involvement. Our data from clinical studies and in an animal model of severe hypertensive nephrosclerosis have strengthened this concept. Conversely, other reports have suggested that uric acid may be a pathogenetic factor. Supporting arguments for this theory maintain that experimental hyperuricemia induces hypertension and renal damage. Epidemiologically, hyperuricemia is associated with hypertension, CHD, renal disease, toxemia of pregnancy, and other outcomes, although mechanisms remain unclear. Additionally, there are no available data on the effects of lowering uric acid on pressure control and organ protection.     

Genetic polymorphisms of the renin-angiotensin system and atheromatous renal artery stenosis

Genes that influence the renin-angiotensin system have been investigated in recent years as potential etiologic candidates of cardiovascular and renal diseases. In atheromatous renal artery stenosis (RAS), a condition characterized by persistent activation of the renin-angiotensin system, the study of these genes may be of particular relevance. We evaluated angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T, and angiotensin II receptor (ATR) A1166C polymorphisms in relation to the occurrence of RAS. We studied 58 patients with angiographically documented RAS; 102 normotensive subjects with normal coronary arteries and no history or clinical or instrumental evidence of atherosclerosis in other vascular districts were considered the control group. Patients had a significantly higher D allele frequency (0.70 versus 0.55; chi(2) 6.88, P=0.01; odds ratio [OR] 1. 9, 95% CI 1.17 to 3.07) than did the control population; 48.3% of patients were homozygous for DD (chi(2) 6.62, P<0.05; OR 2.04, 95% CI 1.05 to 3.95); and only 8.6% carried the II genotype (OR 0.34, 95% CI 0.19 to 1.47). No significant association was found for AGT M235T and ATR A1166C. Our results suggest a predisposing role for ACE genetic polymorphism in the development and progression of atheromatous RAS.