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

Amador, Cristian A; Barrientos, Victor; Peña, Juan; Herrada, Andres A.; Gonzalez, Magdalena; Valdes, Solange; Carrasco, Loreto; Alzamora, Rodrigo; Figueroa, Fernando; Kalergis, Alexis M; Michea, Luis

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.

Más información

Título según WOS: Spironolactone Decreases DOCA-Salt-Induced Organ Damage by Blocking the Activation of T Helper 17 and the Downregulation of Regulatory T Lymphocytes
Título según SCOPUS: Spironolactone decreases DOCA-salt-induced organ damage by blocking the activation of T helper 17 and the downregulation of regulatory T lymphocytes
Título de la Revista: HYPERTENSION
Volumen: 63
Número: 4
Editorial: LIPPINCOTT WILLIAMS & WILKINS
Fecha de publicación: 2014
Página de inicio: 797
Página final: 803
Idioma: English
URL: http://hyper.ahajournals.org/cgi/doi/10.1161/HYPERTENSIONAHA.113.02883
DOI:

10.1161/HYPERTENSIONAHA.113.02883

Notas: ISI, SCOPUS