Aldosterone and mineralocorticoid receptor (MR) activation play key roles in mediating inflammation and vascular injury leading to damage of hearts and kidneys in humans and rodents. The mechanisms by which this occurs are unclear. Two candidates for aldosterone-mediated inflammation are monocyte chemoattractant protein-1 (MCP-1) and 12-lipoxygenase (12-LO), the enzyme responsible for generation of 12- (S)Hydroxyeicosatetraenoate (12-HETE). Individuals with type 2 diabetes and diabetic animals have increased MCP-1 and 12-HETE levels and decreased circulating Mg2+ levels. In humans, low circulating Mg2+ levels are associated with increased inflammation, obesity, diabetes mellitus and increased urinary 12-HETE, suggesting an association between Mg2+ and inflammation. Our preliminary data demonstrate that intracellular Mg2+ is reduced in blood cells from diabetic subjects as compared with nondiabetic subjects. Blood cells (both red blood cells and polymorphonuclear leukocytes [PMN] cells) from human subjects express MR and stimulation of these cells with aldosterone increases Na+/Mg2+ exchanger activity and decreases intracellular Mg2+ levels. Our studies demonstrate that cellular Mg2+ levels are reduced in blood cells from obese, diabetic db/db mice as compared to levels in cells from lean db/+ mice and that treatment with a MR antagonist significantly increases intracellular Mg2+ levels in cells of diabetic mice. Our preliminary studies demonstrate that treatment of diabetic db/db mice with a MR antagonist significantly reduces this inflammation, including decreasing circulating MCP- 1 levels, decreasing 12-LO and MCP-1 mRNA levels, and reducing inflammation in kidney and adipose tissue. Aldosterone appears to directly promote inflammation as we showed that aldosterone increases mRNA levels of MCP-1 in human cells. Infiltration of PMN cells from the circulation into tissue is a key component of aldosterone-induced inflammatory response. We hypothesize that a major mechanism mediating aldosterone's inflammatory effects in diabetes is aldosterone-induced stimulation of Na+/Mg2+ exchanger activity leading to decreases in intracellular Mg2+ resulting in elevated pro-inflammatory factors. We propose a translational research approach involving ex vivo cellular studies in leukocytes isolated from patients with type 2 diabetes that are randomized into a double-blinded trial with spironolactone therapy. We will test our hypothesis through the following Aims: (1) To test the hypothesis that aldosterone stimulates Na+/Mg2+ exchange activity in isolated human leukocytes leading to a decrease in intracellular magnesium and an increase in expression of pro-inflammatory factors. (2) To test the hypothesis that in humans with type 2 diabetes treatment with a MR antagonist will improve measures of cellular Mg2+ homeostasis and inflammation. Understanding the mechanisms by which aldosterone regulates cellular Mg2+, MCP-1, and 12-LO will allow us to develop new strategies to treat inflammation and its consequences in diabetes.

Public Health Relevance

It is a well-established fact that patients with Type 2 diabetes have an increased risk of developing cardiovascular complications such as stroke and arteriosclerosis that is frequently associated with an enhanced inflammatory response. The goal of our research is to understand the mechanisms by which aldosterone mediates inflammation in humans with type 2 diabetes. Understanding these mechanisms will allow us to develop new strategies to treat inflammation and its consequences in diabetes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZHL1-CSR-G (F1))
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Kindzelski, Andrei L
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Brigham and Women's Hospital
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Chong, Cherish; Hamid, Anis; Yao, Tham et al. (2017) Regulation of aldosterone secretion by mineralocorticoid receptor-mediated signaling. J Endocrinol 232:525-534
Tan, Jia W; Gupta, Tina; Manosroi, Worapaka et al. (2017) Dysregulated aldosterone secretion in persons of African descent with endothelin-1 gene variants. JCI Insight 2:
Baudrand, Rene; Gupta, Nidhi; Garza, Amanda E et al. (2016) Caveolin 1 Modulates Aldosterone-Mediated Pathways of Glucose and Lipid Homeostasis. J Am Heart Assoc 5:
Torres-Rasgado, Enrique; Porchia, Leonardo M; Ruiz-Vivanco, Guadalupe et al. (2015) Obese first-degree relatives of patients with type 2 diabetes with elevated triglyceride levels exhibit increased ?-cell function. Metab Syndr Relat Disord 13:45-51
Garza, Amanda E; Rariy, Chevon M; Sun, Bei et al. (2015) Variants in striatin gene are associated with salt-sensitive blood pressure in mice and humans. Hypertension 65:211-217
Nieva-Vazquez, Adriana; PĂ©rez-Fuentes, Ricardo; Torres-Rasgado, Enrique et al. (2014) Serum resistin levels are associated with adiposity and insulin sensitivity in obese Hispanic subjects. Metab Syndr Relat Disord 12:143-8
Coutinho, Patricia; Vega, Christopher; Pojoga, Luminita H et al. (2014) Aldosterone's rapid, nongenomic effects are mediated by striatin: a modulator of aldosterone's effect on estrogen action. Endocrinology 155:2233-43
Baudrand, Rene; Pojoga, Luminita H; Romero, Jose R et al. (2014) Aldosterone's mechanism of action: roles of lysine-specific demethylase 1, caveolin and striatin. Curr Opin Nephrol Hypertens 23:32-7
Rivera, Alicia; Kam, Siok Yuen; Ho, Mengfatt et al. (2013) Ablation of the Kell/Xk complex alters erythrocyte divalent cation homeostasis. Blood Cells Mol Dis 50:80-5
Prado, Gregory N; Romero, Jose R; Rivera, Alicia (2013) Endothelin-1 receptor antagonists regulate cell surface-associated protein disulfide isomerase in sickle cell disease. FASEB J 27:4619-29

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