Lymphocyte responses exacerbate angiotensin II-dependent hypertension

Author:

Crowley Steven D.1,Song Young-Soo1,Lin Eugene E.1,Griffiths Robert1,Kim Hyung-Suk2,Ruiz Phillip3

Affiliation:

1. Division of Nephrology, Department of Medicine, Duke University Medical Center and Durham Veterans Affairs Medical Center, Durham;

2. Department of Pathology, University of North Carolina, Chapel Hill, North Carolina; and

3. Department of Pathology, University of Miami, Miami, Florida

Abstract

Activation of the immune system by ANG II contributes to the pathogenesis of hypertension, and pharmacological suppression of lymphocyte responses can ameliorate hypertensive end-organ damage. Therefore, to examine the mechanisms through which lymphocytes mediate blood pressure elevation, we studied ANG II-dependent hypertension in scid mice lacking lymphocyte responses and wild-type controls. Scid mice had a blunted hypertensive response to chronic ANG II infusion and accordingly developed less cardiac hypertrophy. Moreover, lymphocyte deficiency led to significant reductions in heart and kidney injury following 4 wk of angiotensin. The muted hypertensive response in the scid mice was associated with increased sodium excretion, urine volumes, and weight loss beginning on day 5 of angiotensin infusion. To explore the mechanisms underlying alterations in blood pressure and renal sodium handling, we measured gene expression for vasoactive mediators in the kidney after 4 wk of ANG II administration. Scid mice and controls had similar renal expression for interferon-γ, interleukin-1β, and interleukin-6. By contrast, lymphocyte deficiency (i.e., scid mice) during ANG II infusion led to upregulation of tumor necrosis factor-α, endothelial nitric oxide synthase (eNOS), and cyclooxygenase-2 (COX-2) in the kidney. In turn, this enhanced eNOS and COX-2 expression in the scid kidneys was associated with exaggerated renal generation of nitric oxide, prostaglandin E2, and prostacyclin, all of which promote natriuresis. Thus, the absence of lymphocyte activity protects from hypertension by allowing blood pressure-induced sodium excretion, possibly via stimulation of eNOS- and COX-2-dependent pathways.

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology

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