Involvement of tumor necrosis factor-alpha in angiotensin II-mediated effects on salt appetite, hypertension, and cardiac hypertrophy

Abstract

Hypertension is considered a low-grade inflammatory condition induced by various proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha. Recent studies have implicated an involvement of TNF-alpha in the development of salt-sensitive hypertension induced by angiotensin II (Ang II). To understand further the relationship between TNF-alpha and Ang II, we examined the responses to Ang II in TNF-alpha knockout (TNF-alpha(-/-)) mice in the present study. A continuous infusion of Ang II (1 microg/kg per minute) for 2 weeks was given to both TNF-alpha(-/-) and wild-type (WT) mice with implanted osmotic minipumps. Daily measurement of water intake, salt intake, and urine output were performed using metabolic cages. Blood pressure was monitored continuously with implanted radiotelemetry. Ang II administration for 2 weeks caused increases in salt (0.2+/-0.07 to 5.6+/-0.95 mL/d) and water (5.4+/-0.34 to 11.5+/-1.2 mL/d) intake and in mean arterial pressure (115+/-1 to 151+/-3 mm Hg) in wild-type mice, but these responses were absent in TNF-alpha(-/-) mice (0.2+/-0.04 to 0.3+/-0.09 mL/d, 5.5+/-0.2 to 6.1+/-0.07 mL/d, and 113+/-2 to 123+/-3 mm Hg, respectively). Cardiac hypertrophy induced by Ang II was significantly attenuated in TNF-alpha(-/-) mice compared with wild-type mice. In a group of TNF-alpha(-/-) mice, when replacement therapy was made with recombinant TNF-alpha, Ang II induced similar responses in salt appetite, mean arterial pressure, and cardiac hypertrophy, as observed in wild-type mice. These results suggest that TNF-alpha plays a mechanistic role in mediating chronic Ang II-induced effects on salt appetite and blood pressure, as well as on cardiac hypertrophy.

Figure 1

Effect of Ang II on mean arterial pressure. Mean arterial pressure was measured using radiotelemetry for the period of Ang II infusion. Values are means ±SEMs (n=6 animals per group). P<0.05 vs *WT group and #TNF-α ^−/− group.

Figure 2

Effect of Ang II on water (A) and salt (1.8% NaCl) intake (B) and on urine excretion (C). Ang II was infused from day 1 to day 14. Values are means±SEMs (n=6 animals per group). P<0.05 vs *WT group and #TNF-α ^−/−group.

Figure 3

Effect of Ang II on cardiac hypertrophy. A, Heart weight:body weight ratio in WT and TNF-α ^−/− mice. B, mRNA expression of atrial natriuretic peptide in the left ventricle. Values are means±SEMs. P<0.05 vs *WT group and #TNF-α^−/− group.

Figure 4

Effect of Ang II on mRNA expression. A, AT₁ receptor in left ventricle. B, AT₁ receptor in hypothalamus. C, NF-κB in left ventricle. Values are means±SEMs. P<0.05 vs *WT group and #TNF-α ^−/− group.

Figure 5

Effect of Ang II on protein expression of AT₁ receptor (AT₁R). Representative Western blot and densitometric analysis of AT₁R protein in left ventricle (A) and hypothalamus (B). *P<0.05 vs WT group.