Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis
Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis
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DOI：
10.1161/circulationaha.115.018226
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发表时间：
2015-12-01
期刊：
影响因子：
37.8
通讯作者：
de Chantemele, Eric J. Belin
中科院分区：
文献类型：
--
作者：
Huby, Anne-Cecile;Antonova, Galina;de Chantemele, Eric J. Belin
背景在肥胖中，醛固酮的过度合成有助于代谢和心血管功能障碍的发生和发展。肥胖引起的醛固酮增多症独立于已知的醛固酮分泌调节因子，但依赖于未知的脂肪细胞衍生因子。我们假设脂肪因子瘦素是醛固酮合成酶(CYP11B2)表达和醛固酮释放的直接调节因子，并通过醛固酮依赖的机制促进心血管功能障碍。方法与结果对人肾上腺横断面和肾上腺皮质细胞进行免疫组化染色，发现肾上腺皮质细胞共表达CYP11B2和瘦素受体。肾上腺细胞色素P11B2的表达和血浆醛固酮水平的测量表明，内源性(肥胖)或外源性(输注)瘦素的增加呈剂量依赖性地增加细胞色素P11B2的表达和醛固酮，而不增加血浆血管紧张素II、血钾或皮质酮。血管紧张素II受体既不能阻断NOR，也不能抑制肾上腺素能受体抑制瘦素诱导的醛固酮分泌。在培养的肾上腺皮质细胞中也得到了相同的结果。增强的瘦素信号增加了CYP11B2的表达和血浆醛固酮，而瘦素或瘦素受体的缺陷减弱了肥胖诱导的CYP11B2和醛固酮的增加，排除了肥胖本身的作用。在肾上腺皮质细胞中，瘦素增加了细胞内钙离子，增加了钙调蛋白和钙调蛋白激酶II的表达，而钙离子螯合作用减弱了瘦素介导的细胞色素P11B2的增加。盐皮质激素受体拮抗瘦素诱导的内皮功能障碍和心脏纤维化标志物的增加。结论瘦素是一种新的醛固酮合成调节剂，直接作用于肾上腺肾小球细胞，通过钙依赖机制增加细胞色素P11B2的表达，促进醛固酮的产生。此外，瘦素介导的醛固酮分泌通过促进心脏内皮细胞功能障碍和促纤维化标志物的表达而促进心血管疾病。
Background In obesity, the excessive synthesis of aldosterone contributes to the development and progression of metabolic and cardiovascular dysfunctions. Obesity-induced hyperaldosteronism is independent of the known regulators of aldosterone secretion, but reliant on unidentified adipocyte-derived factors. We hypothesized that the adipokine leptin is a direct regulator of aldosterone synthase (CYP11B2) expression and aldosterone release and promotes cardiovascular dysfunction via aldosterone-dependent mechanisms.Methods and Results Immunostaining of human adrenal cross-sections and adrenocortical cells revealed that adrenocortical cells coexpress CYP11B2 and leptin receptors. Measurements of adrenal CYP11B2 expression and plasma aldosterone levels showed that increases in endogenous (obesity) or exogenous (infusion) leptin dose-dependently raised CYP11B2 expression and aldosterone without elevating plasma angiotensin II, potassium or corticosterone. Neither angiotensin II receptors blockade nor and adrenergic receptors inhibition blunted leptin-induced aldosterone secretion. Identical results were obtained in cultured adrenocortical cells. Enhanced leptin signaling elevated CYP11B2 expression and plasma aldosterone, whereas deficiency in leptin or leptin receptors blunted obesity-induced increases in CYP11B2 and aldosterone, ruling out a role for obesity per se. Leptin increased intracellular calcium, elevated calmodulin and calmodulin-kinase II expression, whereas calcium chelation blunted leptin-mediated increases in CYP11B2, in adrenocortical cells. Mineralocorticoid receptor blockade blunted leptin-induced endothelial dysfunction and increases in cardiac fibrotic markers.Conclusions Leptin is a newly described regulator of aldosterone synthesis that acts directly on adrenal glomerulosa cells to increase CYP11B2 expression and enhance aldosterone production via calcium-dependent mechanisms. Furthermore, leptin-mediated aldosterone secretion contributes to cardiovascular disease by promoting endothelial dysfunction and the expression of profibrotic markers in the heart.