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Objective: Aldosterone production by the adrenal gland is mainly regulated by the renin-angiotensin system (RAS), which is normally suppressed by a high-salt diet. However, plasma aldosterone levels are elevated in proportion to the severity of heart failure even if caused by high-salt intake. The inappropriate increase in plasma aldosterone level could not be diminished by pharmacological blockade of the RAS. We investigated the cellular mechanism underlying the aberrant aldosterone production in heart failure beyond the activation of RAS. Methods and Results: Dahl-salt sensitive rats fed high salt diet developed malignant hypertension, resulting in heart failure with increased plasma aldosterone level. The gene expression pattern of the adrenal gland from heart failure rats showed strikingly upregulated β3-adrenergic receptor (β3-AR) expression. Immunohistochemical staining confirmed that heart failure increased β3-AR expression in zona glomerulosa cells in adrenal gland of Dahl-salt sensitive rats. And the staining of pimonidazole, a hypoxia probe, revealed that the outer layer of adrenal cortex in the heart failure rat was under hypoxic condition. Hypoxia and DMOG, a chemical stabilizer of hypoxia-inducible factor, strongly induced β3-AR mRNA expression in H295R human adrenocortical carcinoma cells. Hypoxia-reoxygenation stimuli induced aldosterone production from H295R cells, which was blocked by SR59230A, a selective β3-AR antagonist, but not by losartan, an angiotensin II receptor blocker (ARB). Hypoxia endowed catecholamine responsiveness in H295R cells by increased β3-AR expression, wherein β3-AR agonist increased the phosphorylation levels of hormone-sensitive lipase (HSL) through activation of ERK pathway. Conclusions: In the present study, we demonstrated that the β3-AR induction in adrenal gland by hypoxia played an important role in aberrant aldosterone production in heart failure. The catecholamine stimuli through β3-AR in adrenocortical cells caused the ERK-mediated phosphorylation of HSL, suggesting that the HSL promotes lipolysis to supply substrates for the aldosterone biosynthesis.

Background: (Pro)renin receptor[(P)RR] is a single trans-membrane receptor that binds to both renin and its precursor prorenin to activate tissue renin-angiotensin system (RAS). (P)RR is cleaved by furin to generate soluble (pro)renin receptor [s(P)RR], which is secreted into the extracellular space. Blood s(P)RR level is a candidate biomarker reflecting the status of the tissue RAS, and we have reported that serum s(P)RR levels are associated with renal function. Endocrine or metabolic factors contribute to progression of endorgan damages in hypertensive patients. Therefore, in the present study, we investigated the relationships between serum s(P)RR levels and endocrine or metabolic factors in patients with essential hypertension. Methods: We measured serum s(P)RR levels and assessed the relationships between serum s(P)RR levels and background factors including endocrine or metabolic factors such as age, body mass index (BMI), abdominal circumference, hemoglobin, uric acid, HbA1c, LDL-cholesterol (C), HDL-C, triglyceride (TG), high-sensitivity (hs) CRP, plasma renin activity, aldosterone concentration, noradrenaline, adrenaline, thyroid stimulating hormone, free T3, and free T4 in essential hypertensive patients. Results: A total of 302 patients (138 males) were enrolled. The mean value for age was 57±12 y.o., BMI was 24.9±5.1 Kg/m2, blood pressure was 140±16/85±12 mmHg, hemoglobin was 14.0±1.3 g/dl, estimated glomerular filtration rate (eGFR) was 75.2±20.6 ml/min/1.73 m2, HbA1c was 5.7±0.7%, and serum s(P)RR level was 21.0±5.8 ng/ml. Serum s(P)RR levels were significantly positively correlated with age (r=0.209, p Conclusion: In patients with essential hypertension, serum s(P)RR levels were shown to be associated with endocrine or metabolic factors in addition to renal function, suggesting serum s(P)RR level as a useful biomarker that reflects the status of endocrine or metabolic disorders.

Numerous clinical trials demonstrated that renin-angiotensin-aldosterone system (RAAS) was involved in the pathogenesis of hypertension-induced heart failure. While RAS is a major machinery required for aldosterone production, multiple minor systems, including catecholamine, could give rise to the aberrant aldosterone production beyond the RAS activation. We investigated the mechanism underlying the RAS-independent aldosterone production in heart failure. Dahl-salt sensitive rats fed high salt diet developed malignant hypertension, resulting in heart failure with inappropriately increased plasma aldosterone level. The gene expression pattern of the adrenal gland from heart failure rats showed strikingly upregulated b3-Adrenergic receptor (b3-AR) expression. Using Dahl-salt sensitive rats and H295R human adrenocortical carcinoma cells, we conducted immunohistochemical and molecular biological studies to assess whether b3-AR contribute to aldosterone production in heart failure. Immunohistochemical staining confirmed that heart failure increased b3-AR expression in zona glomerulosa cells in adrenal gland of Dahl-salt sensitive rats. And the staining of pimonidazole, a hypoxia probe, revealed that the outer layer of adrenal cortex in the heart failure rat was under hypoxic condition. Hypoxia and DMOG, a chemical stabilizer of hypoxia-inducible factor, strongly induced b3-AR mRNA expression in H295R cells. Hypoxia-reoxygenation stimuli induced aldosterone production from H295R cells, which was blocked by SR59230A, a selective b3-AR antagonist, but not by losartan, an angiotensin II receptor blocker (ARB). Hypoxia endowed catecholamine responsiveness in H295R cells by increased b3-AR expression, wherein b3-AR agonist increased the phosphorylation levels of hormone-sensitive lipase (HSL) through activation of ERK pathway. In the present study, we demonstrated that the b3-AR induction in adrenal gland by hypoxia played an important role in aberrant aldosterone production in heart failure. The b3-AR-mediated catecholamine system could regulate the utilization of cholesterol, a substrate of aldosterone, via the ERK-HSL pathway.