title: Spironolactone decreases DOCA-salt-induced organ damage by blocking the activation of T helper 17 and the downregulation of regulatory T lymphocytes.
abstract: 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.
authors.affiliation: Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile. lmichea@med.uchile.cl.
authors.forename: Cristián A
authors.initials: CA
authors.lastname: Amador
authors.forename: Víctor
authors.initials: V
authors.lastname: Barrientos
authors.forename: Juan
authors.initials: J
authors.lastname: Peña
authors.forename: Andrés A
authors.initials: AA
authors.lastname: Herrada
authors.forename: Magdalena
authors.initials: M
authors.lastname: González
authors.forename: Solange
authors.initials: S
authors.lastname: Valdés
authors.forename: Loreto
authors.initials: L
authors.lastname: Carrasco
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Alzamora
authors.forename: Fernando
authors.initials: F
authors.lastname: Figueroa
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Kalergis
authors.forename: Luis
authors.initials: L
authors.lastname: Michea
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D064791:Desoxycorticosterone Acetate / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000502:physiology; D006331:Heart Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D006973:Hypertension / Q000139:chemically induced* / Q000150:complications / Q000503:physiopathology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D007674:Kidney Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013148:Spironolactone / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects* / Q000473:pathology
chemical_list: D000906:Antibodies; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D020381:Interleukin-17; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D064791:Desoxycorticosterone Acetate
keywords: aldosterone; fibrosis; hypertension; inflammation; interleukin-17; receptors, mineralocorticoid