Spironolactone Decreases DOCA-Salt-Induced Organ Damage by Blocking the Activation of T Helper 17 and the Downregulation of Regulatory T Lymphocytes
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.
|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|
|Editorial:||LIPPINCOTT WILLIAMS & WILKINS|
|Fecha de publicación:||2014|
|Página de inicio:||797|