Obesity hypertension and metabolic syndrome have become major public health concerns. Nowadays, aldosterone is recognized as an important mediator of cardiovascular and renal damage. In the

kidney, aldosterone injures glomerular visceral epithelial cells (podocytes), the final filtration barrier to plasma macromolecules, leading to proteinuria and glomerulosclerosis.

Mineralocorticoid receptor (MR) antagonists effectively ameliorate proteinuria in patients or in animal models of hypertension, diabetes mellitus and chronic kidney disease (CKD), as well as

in patients who experience ‘aldosterone breakthrough.’ Recently, clinical and experimental studies have shown that plasma aldosterone concentration is associated with obesity hypertension

renal and cardiac injuries. Adipocyte-derived aldosterone-releasing factors (ARFs), although still unidentified, may account for aldosterone excess and the resultant target organ

complication in SHR/cp. On the other hand, recent studies have shown that MR activation triggers target organ disease even in normal or low aldosterone states. We identified a small GTP

(guanosine triphosphate)-binding protein, Rac1, as a novel activator of MR, and showed that this ligand-independent MR activation by Rac1 contributes to the nephropathy of several CKD

models. We expect that ARFs and Rac1 can be novel therapeutic targets for metabolic syndrome and CKD. Future large-scale clinical trials are awaited to prove the efficacy of MR blockade in

patients with obesity hypertension and metabolic syndrome.

The modern sedentary lifestyle, unhealthy food with too much fat and salt, physical inactivity and psychological stress have led to a global epidemic of obesity in the last few decades.1, 2

In particular, obesity hypertension and metabolic syndrome have become major public health concerns.3, 4 According to the 2006 National Health and Nutrition Survey in Japan, one out of two

men and one out of five women aged between 40 and 74 years are suffering from metabolic syndrome or are sufferers-to-be.

Recently, the nuclear receptor superfamily has been postulated as key molecules in metabolic syndrome.5, 6, 7 The nuclear receptors are ligand-activated transcription factors whose activity

is regulated by small lipophilic molecules that include steroid hormones, fat-soluble vitamins, thyroid hormone, retinoids and dietary lipids, and control genes involved in glucose, lipid

and energy metabolism.8 The family also includes orphan nuclear receptors, such as peroxisome proliferator-activated receptor (PPAR)-α, γ, δ, liver X receptor and farnesoid X receptor.

Indeed, genetically engineered mice of estrogen receptor,9 androgen receptor,10 glucocorticoid activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1),11 PPAR-γ12 and PPAR-δ13

were reported to develop visceral obesity and metabolic syndrome. On the other hand, the renin–angiotensin–aldosterone system (RAAS) is also implicated in the pathogenesis of metabolic

syndrome.14, 15 Aldosterone is a component of the RAAS and its receptor mineralocorticoid receptor (MR) belongs to the nuclear receptor superfamily. Recent studies have suggested an

etiological role for aldosterone/MR in the development of metabolic syndrome. On the other hand, the aldosterone/MR system also has a critical role in the progression of target organ damage

in metabolic syndrome. We have shown that renal and cardiac injuries in an experimental model of metabolic syndrome are strongly dependent on the activation of the aldosterone/MR system.16,

17, 18 In addition, MR activation causes target organ damage even in normal or low aldosterone states.19, 20 We identified a small guanosine triphosphate (GTP)-binding protein, Rac1, as a

novel mediator of ligand-independent MR activation, and cross-talk between Rac1 and MR contributes to the nephropathy of several chronic kidney disease (CKD) models.21

The human MR gene has two alternative promoters, P1 and P2. The transgenic expression of SV40 large T antigen driven by the P1 promoter resulted in lethal hibernomas, unraveling a new

functional link between aldosterone and energy homeostasis in brown adipose tissues.22, 23 Overexpression of human MR under the control of the P1 promoter resulted in abnormal urinary

electrolyte excretion and dilated cardiomyopathy-like cardiac lesion, supporting the role in cardiovascular disease (CVD) and CKD.24

In this review, we first provide a general overview of obesity and hypertension and then focus on the link between aldosterone/MR and metabolic syndrome. Finally, we introduce our recent

findings on the roles of aldosterone-dependent and aldosterone-independent MR activation in target organ complication associated with metabolic syndrome.

Both genetic and environmental factors contribute to the development of hypertension. Recent genome-wide association studies of BP and hypertension identified several loci associated with

hypertension.25, 26 On the other hand, obesity is shown to be one of the major environmental factors to increase the risk of hypertension.

Obesity, especially visceral obesity, is closely related to hypertension.27, 28, 29, 30 Blood pressure (BP) increases ∼4.5 mm Hg for every 10 lb (4.5 kg) weight gain.31 During a 4-year

follow-up, 5% weight gain was associated with 20–30% increased odds of hypertension.29 According to the Framingham Heart Study, 65–75% of the risk for hypertension is attributed to excess

weight.28 Both obesity and hypertension convey increased risk for CVD. In addition, visceral obesity and hypertension often cluster with insulin resistance, dyslipidemia, inflammation and

prothrombotic states.3, 32 This risk-factor clustering condition, known as metabolic syndrome, is a highly predisposing condition for target organ injury.33, 34 Furthermore, high salt intake

increases BP and worsens cardiovascular and renal outcomes in patients with obesity and metabolic syndrome.35, 36, 37, 38

Several candidate chromosomal loci or single nucleotide polymorphisms (SNPs) are postulated. For example, a whole-genome scan suggests a locus at 1p36 for obesity hypertension.39 Genetic

studies in humans suggest the association of obesity hypertension with variants of several genes, including tumor necrosis factor-α (TNF-α),40 glucocorticoid receptor,41 CYP11B242 and serum

and glucocorticoid-regulated kinase (Sgk)1.43 Diseases of civilization, including obesity and hypertension, may result from the mismatch between contemporary environment and ‘energy-thrifty

genotype’ of genes, which helped our ancestors survive occasional famines.44, 45 According to the ‘fetal programming of adult disease’ hypothesis proposed by Barker et al.,46 obesity and

metabolic syndrome in adulthood originate from malnutrition of the fetus during intrauterine life, which leads to functional and structural adaptive processes for its survival and a

compensatory catch-up growth.

Obese subjects have increased cardiac output and plasma volume as well as reduced peripheral vascular resistance. Enhanced renal tubular sodium reabsorption has a central role in the

pathogenesis of obesity hypertension. According to Guyton's theory,47 sodium retention impairs pressure natriuresis; higher pressure is necessary for maintaining a sodium balance, resulting

in hypertension (right shift in the pressure-natriuresis curve). Multiple factors are postulated to contribute to the enhanced sodium reabsorption, as described below (Figure 1).48, 49, 50

Mechanisms of obesity hypertension. Activation of the sympathetic nervous system (SNS), renin–angiotensin system (RAS), aldosterone, hyperinsulinemia and mechanical compression of the kidney

cause increased renal tubular sodium reabsorption and hypertension. Adipocyte-derived factors, such as leptin, angiotensinogen and aldosterone-releasing factors, are supposed to have

important roles. TNF-α, tumor necrosis factor-α.

Renal sympathetic overactivity increases sodium reabsorption and vasoconstriction. Leptin, an adipokine secreted in proportion to adiposity, is believed to be an important mediator linking

obesity, renal sympathetic activation and hypertension. Leptin acts on the ventromedial and dorsomedial hypothalamic nuclei and regulates energy homeostasis by reducing appetite and

increasing energy expenditure. It also modulates renal sympathetic outflow through the melanocortin system. Obesity may cause ‘selective leptin resistance,’ whereby the sympathetic nervous

system (SNS) responses to leptin are maintained, whereas its anorexic effect is blunted.51 Renal sympathetic activation is also caused by insulin, non-esterified fatty acids, angiotensin II

and aldosterone.

Despite marked sodium retention, obesity hypertension is associated with activation of the renin–angiotensin system (RAS). The increased renin secretion may be caused by the increased

sympathetic stimulation. Alternatively, angiotensinogen produced by the adipose tissue may contribute to the high circulating angiotensinogen levels in obesity hypertension.15 Overexpression

of 11β-HSD1 in the adipose tissue results in visceral obesity and metabolic syndrome. The mice had increased angiotensinogen in the plasma and in the adipose tissue, and hypertension was

abolished by angiotensin II type 1 receptor antagonist (ARB).52

Obese subjects are characterized by hyperinsulinemia and insulin resistance. Hyperinsulinemia could increase sympathetic activity and sodium reabsorption, modify ion transport and stimulate

proliferation of smooth muscle cells.

Similar to the case of leptin, insulin actions are blunted in the muscle and adipose tissues, whereas renal action is preserved and facilitated by hyperinsulinemia, resulting in enhanced

sodium absorption. The former actions are mediated by insulin receptor substrates (IRS)-1, and the latter by IRS-2.53

Visceral fat mass may compress the kidney and increase tubular reabsorption. Changes in the renal medullary histology may increase interstitial hydrostatic pressure, compress the thin loops

of Henle and vasa recta and enhance tubular reabsorption.

Aldosterone excess has been implicated in obesity-related disorders.

In 1981, Tuck et al.54 first suggested the involvement of aldosterone in the pathogenesis of obesity-associated hypertension. They indicated that weight reduction decreased plasma renin

activity and aldosterone concentration, along with BP in obese patients. A recent study by Engeli et al.55 showed that in menopausal women, the obese group had higher plasma aldosterone

compared with the lean group (62±25 vs. 38±17 ng l−1), and that weight reduction (−5%) by caloric restriction was accompanied by a reduction in BP (−7 mm Hg) and plasma aldosterone (−31%).

Similarly, patients with visceral-type morbid obesity (body mass index 49.0±3.5 kg m−2) had increased plasma aldosterone concentration (1070±137 pM, normal: 190–932 pM), which was

significantly reduced (699±90 pM) after the correction of body mass index (27.7±2.0 kg m−2) by gastric bypass surgery. Morbidly obese patients of subcutaneous type had lower plasma

aldosterone levels (810±103 pM).56 Goodfriend et al.57, 58 showed a relationship between plasma aldosterone concentration and the amount of visceral fat, which was independent of renin.

Accordingly, non-classical adrenal stimuli for aldosterone production had been reported, including oxidized products of linoleic acid59 and as-yet-unidentified potent

mineralocorticoid-releasing factors secreted by adipocytes.60

Recent clinical evidence supports the intimate relationship between aldosterone and metabolic syndrome. Two cross-sectional clinical studies of African descent have shown that plasma

aldosterone concentration is independently associated with metabolic syndrome.61, 62 The C allele of the −344C/T variant in the promoter of the aldosterone synthase (CYP11B2) gene, which is

associated with hyperaldosteronemia, was shown to increase susceptibility to metabolic syndrome in European men.42 Fallo et al.63 observed that patients with primary aldosteronism had a

higher incidence of metabolic syndrome than those with essential hypertension (41.1 vs. 29.6%; P4.31 kg. Aldosterone as well as glucocorticoid is suggested to be involved in the mechanisms,

possibly because of the activation of the hypothalamus–pituitary–adrenal axis.66

Aldosterone excess has also been reported in several animal models of obesity and metabolic syndrome. For example, obese, heart failure-prone SHHF/Mcc-fa cp is documented to have a higher

plasma aldosterone level compared with +/+ control (209.4±14.3 vs. 107.0±17.0 ng l−1; P