Spironolactone Decreases DOCA–Salt–Induced Organ Damage by Blocking the Activation of T Helper 17 and the Downregulation of Regulatory T Lymphocytes

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 63; no. 4; pp. 797 - 803
• Main Authors: Amador, Cristián A, Barrientos, Víctor, Peña, Juan, Herrada, Andrés A, González, Magdalena, Valdés, Solange, Carrasco, Loreto, Alzamora, Rodrigo, Figueroa, Fernando, Kalergis, Alexis M, Michea, Luis
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.04.2014; Lippincott Williams & Wilkins
• Subjects: Animals; Antibodies - immunology; Antibodies - pharmacology; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Desoxycorticosterone Acetate - adverse effects; Desoxycorticosterone Acetate - pharmacology; Disease Models, Animal; Down-Regulation - drug effects; Down-Regulation - physiology; Forkhead Transcription Factors - drug effects; Forkhead Transcription Factors - physiology; Heart Diseases - etiology; Heart Diseases - physiopathology; Heart Diseases - prevention & control; Hypertension - chemically induced; Hypertension - complications; Hypertension - physiopathology; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - immunology; Interleukin-17 - physiology; Kidney Diseases - etiology; Kidney Diseases - physiopathology; Kidney Diseases - prevention & control; Male; Medical sciences; Mineralocorticoid Receptor Antagonists - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid - drug effects; Receptors, Mineralocorticoid - physiology; Signal Transduction - drug effects; Signal Transduction - physiology; Spironolactone - pharmacology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - pathology; Th17 Cells - drug effects; Th17 Cells - pathology; Potassium sparing diuretic; Mineralocorticoid; receptors, mineralocorticoid; Cardiovascular disease; Activation; Aldosterone; Salt; Regulation(control); Spironolactone; Immunological investigation; T-Lymphocyte; Cardiology; Biological receptor; Hypertension; Steroid hormone; Blocking; Inflammation; Interleukin 17; Aldosterone antagonist; interleukin-17; Decrease; Adrenal hormone; Fibrosis; Circulatory system; Organ; fibrosis; inflammation; hypertension; aldosterone
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.113.02883

Adaptive immune response has been implicated in inflammation and fibrosis as a result of exposure to mineralocorticoids and a high-salt diet. We hypothesized that in mineralocorticoid-salt–induced hypertension, activation of the mineralocorticoid receptor alters the T-helper 17 lymphocyte (Th17)/regulatory T-lymphocyte/interleukin-17 (IL-17) pathway, contributing to cardiac and renal damage. We studied the inflammatory response and tissue damage in rats treated with deoxycorticosterone acetate and high-salt diet (DOCA–salt), with or without mineralocorticoid receptor inhibition by spironolactone. To determine whether Th17 differentiation in DOCA–salt rats is caused by hypertension per se, DOCA–salt rats received antihypertensive therapy. In addition, to evaluate the pathogenic role of IL-17 in hypertension and tissue damage, we studied the effect of IL-17 blockade with a specific antibody (anti–IL-17). We found activation of Th17 cells and downregulation of forkhead box P3 mRNA in peripheral tissues, heart, and kidneys of DOCA–salt–treated rats. Spironolactone treatment prevented Th17 cell activation and increased numbers of forkhead box P3–positive cells relative to DOCA–salt rats. Antihypertensive therapy did not ameliorate Th17 activation in rats. Treatment of DOCA–salt rats with anti–IL-17 significantly reduced arterial hypertension as well as expression of profibrotic and proinflammatory mediators and collagen deposits in the heart and kidney. We conclude that mineralocorticoid receptor activation alters the Th17/regulatory T-lymphocyte/IL-17 pathway in mineralocorticoid-dependent hypertension as part of an inflammatory mechanism contributing to fibrosis.