Lymphocyte responses exacerbate angiotensin II-dependent hypertension

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-gamma, interleukin-1beta, and interleukin-6. By contrast, lymphocyte deficiency (i.e., scid mice) during ANG II infusion led to upregulation of tumor necrosis factor-alpha, 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 E(2), 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.

Fig. 1.

C3H SCID mice have a blunted chronic hypertensive response to ANG II. Hemodynamic parameters were measured by radiotelemetry in the experimental groups at baseline (“pre”) and during 3 wk of ANG II infusion. Values during ANG II are averaged over 5-day periods. A: mean arterial pressures. *P < 0.04 vs. C3H. †P = 0.03 vs. C3H. ‡P < 0.005 vs. C3H. #P = 0.05 vs. C3H. B: systolic blood pressures. †P = 0.02 vs. C3H. #P < 0.08 vs. C3H. C: diastolic blood pressures. *P < 0.02 vs. C3H. †P = 0.02 vs. C3H. ‡P = 0.0006 vs. C3H. #P < 0.05 vs. C3H. D: heart rates. *P < 0.04 vs. C3H Scid baseline, P < 0.04 vs. C3H Scid day 10. †P < 0.007 vs. C3H baseline. n ≥ 7 mice/group.

Fig. 2.

Reduced cardiac hypertrophy and injury in SCID mice infused with ANG II. A: heart weight-to-body weight ratios (mg/g) in the experimental groups following 28 days of ANG II infusion or saline control. *P < 0.0001 vs. C3H saline. †P < 0.0002 vs. C3H Scid saline and P = 0.0007 vs. C3H ANG II. B: representative heart section from C3H ANG II group showing mild myocardial injury, mononuclear cell infiltrates, fibrosis, and chronic vascular damage. C: representative heart section from C3H Scid ANG II group (×20).

Fig. 3.

Lymphocyte deficiency in SCID mice reduces hypertensive kidney injury. A: urinary albumin excretion (μg/mg creatinine) in the experimental groups following 25 days of ANG II infusion or saline control. *P = 0.002 vs. C3H saline. †P < 0.05 vs. C3H Scid saline, P = 0.02 vs. C3H ANG II. B: representative kidney section from C3H group showing mild mesangial expansion, sparse mononuclear cell infiltrates, and fibrosis. C: representative kidney section from C3H Scid group (×20).

Fig. 4.

Nitric oxide (NO) production is exaggerated in ANG II-infused SCID mice. A: urinary excretion of nitrate/nitrite metabolites of NO on day 5 of ANG II infusion. *P < 0.04 vs. C3H. B: real-time PCR for endothelial nitric oxide synthase (eNOS) mRNA expression in kidney following 28 days of saline or ANG II infusion. *P < 0.03 vs. C3H ANG II.

Fig. 5.

Tumor necrosis factor (TNF)-α expression is augmented in SCID kidneys following ANG II infusion. A: levels of mRNA for TNF-α and housekeeping gene L32 assessed by RNase protection assay in kidney following 28 days of ANG II infusion. B: plot of the corresponding analysis by densitometry; the lanes were run on the same gel but were noncontiguous. *P = 0.01 vs. C3H.

Fig. 6.

SCID mice have enhanced renal cyclooxygenase (COX)-2 expression and urinary excretion of vasodilatory prostaglandins in ANG II-dependent hypertension. A: relative expression in kidney of COX-1 and COX-2 after 28 days of ANG II infusion. *P = 0.05 vs. C3H wild type (WT). B and C: urinary excretion of metabolites for prostaglandin E₂ (B) and prostacyclin (prostaglandin I₂) (C) measured by ELISA following 25 days of ANG II infusion. *P = 0.05 vs. C3H WT.