Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension

Abstract

Immune system activation contributes to the pathogenesis of hypertension and the resulting progression of chronic kidney disease. In this regard, we recently identified a role for proinflammatory Th1 T-lymphocyte responses in hypertensive kidney injury. Because Th1 cells generate interferon-γ and tumor necrosis factor-α (TNF-α), we hypothesized that interferon-γ and TNF-α propagate renal damage during hypertension induced by activation of the renin-angiotensin system. Therefore, after confirming that mice genetically deficient of Th1 immunity were protected from kidney glomerular injury despite a preserved hypertensive response, we subjected mice lacking interferon-γ or TNF-α to our model of hypertensive chronic kidney disease. Interferon deficiency had no impact on blood pressure elevation or urinary albumin excretion during chronic angiotensin II infusion. By contrast, TNF-deficient (knockout) mice had blunted hypertensive responses and reduced end-organ damage in our model. As angiotensin II-infused TNF knockout mice had exaggerated endothelial nitric oxide synthase expression in the kidney and enhanced nitric oxide bioavailability, we examined the actions of TNF-α generated from renal parenchymal cells in hypertension by transplanting wild-type or TNF knockout kidneys into wild-type recipients before the induction of hypertension. Transplant recipients lacking TNF solely in the kidney had blunted hypertensive responses to angiotensin II and augmented renal endothelial nitric oxide synthase expression, confirming a role for kidney-derived TNF-α to promote angiotensin II-induced blood pressure elevation by limiting renal nitric oxide generation.

Keywords: angiotensin II; hypertension; interferon-gamma; kidney; tumor necrosis factor-alpha.

Figure 1

Th1 immune responses exaggerate urinary excretion of nephrin in Ang II-dependent hypertension. A, Systolic and B, Diastolic blood pressures measured by radiotelemetry in the experimental groups at baseline (“pre”) and during chronic Ang II infusion. Wild-type (WT), circles. T-bet KO (KO), squares. n = 7 per group. C, Urinary nephrin excretion (μg/24hrs) after 25 days of Ang II.

Figure 2

TNF-α potentiates Ang II-induced hypertension and cardiac hypertrophy. A, Mean arterial blood pressures measured by radiotelemetry in wild-type (WT) and TNF-α-deficient (KO) groups at baseline (“pre”) and during 3 weeks of chronic Ang II infusion. WT, circles. KO, triangles. n = 9 per group. B, Ratio of heart weight/body weight (mg/g) after 28 days of Ang II.

Figure 3

TNF-α contributes to the progression of hypertensive CKD. A, Urinary albumin and B, nephrin excretion (μg/24hrs) in wild-type (WT) and TNF KO (KO) groups after 25 days of Ang II. C–D, Representative images of kidney sections from (C) WT and (D) TNF KO groups. E, Semi-quantitative kidney injury scores calculated per Methods after 4 weeks of Ang II.

Figure 4

TNF-α suppresses generation of nitric oxide (NO) in the kidney during hypertension. A, mRNA expression of renin, IL-1b, eNOS, and NGAL in the WT and TNF KO kidneys measured by real-time PCR after 4 weeks of Ang II. B, Total urinary excretion of NO metabolites after 25 days of Ang II.

Figure 5

Ang II mediates blood pressure elevation through TNF-α generated in the kidney. A, Mean arterial blood pressures measured by radiotelemetry in wild-type recipients of TNF KO kidneys (KO→WT, triangles) or wild-type kidneys (WT→WT, circles) at baseline (“pre”) and during 3 weeks of Ang II infusion. * P=0.04 for baseline, #P=0.02 over Ang II infusion period, n 6 per group. B, Ratio of heart weight/body weight (mg/g) after 4 weeks of Ang II. C–D, Urinary excretion of (C) albumin (μg/mg creatinine) and (D) nephrin (μg/24hrs) following 4 weeks of Ang II.

Figure 6

Renal generation of nitric oxide (NO) in kidney transplantation groups. A, mRNA expression of eNOS measured by real-time PCR in the transplanted kidney after 4 weeks of Ang II. B, Urinary excretion of NO in the transplant groups at day 25 of Ang II.