Tumor Necrosis Factor-α Antagonist Etanercept Decreases Blood Pressure and Protects the Kidney in a Mouse Model of Systemic Lupus Erythematosus

Abstract

Abstract-Chronic inflammation has been implicated in the pathology of hypertension; however, the role for specific cytokines remains unclear. We tested whether tumor necrosis factor-␣ blockade with etanercept (Etan) reduces mean arterial pressure in a female mouse model of systemic lupus erythematosus (SLE). SLE is a chronic inflammatory disorder with prevalent hypertension. and lowered in Etan-treated SLE mice (6645Ϯ490). Renal cortex nuclear factor B (phosphorylated and nonphosphorylated) was increased in SLE mice compared with controls and lower in Etan-treated SLE mice. These data suggest that TNF-␣ mechanistically contributes to the development of hypertension in a chronic inflammatory disease through increased renal nuclear factor B, oxidative stress, and inflammation. (Hypertension. 2010;56:643-649.) Key Words: systemic lupus erythematosus Ⅲ hypertension Ⅲ inflammation Ⅲ TNF-␣ Ⅲ oxidative stress Ⅲ cytokine A growing body of literature suggests that chronic inflammation plays an important role in the progression of several forms of hypertension. Plasma levels of inflammatory cytokines, such as tumor necrosis factor-␣ (TNF-␣) and interleukin 6, directly correlate with blood pressure and essential hypertension in humans. 1,2 In addition, recent studies demonstrate that immunosuppressive therapy with mycophenolate mofetil reduced blood pressure in essential hypertensive patients 3 and in experimental animal models of hypertension. 4 The potential mechanistic role of specific inflammatory cytokines, such as TNF-␣, in the development of hypertension remains unclear. For example, the effect of TNF-␣ blockade in experimental models of hypertension varies, ranging from having no effect on pressure 5,6 to delaying the progression 7 or even completely ameliorating hypertension. 8 Therefore, further studies to understand the contribution of this master immune regulator to the development of hypertension are warranted.Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder of unknown etiology that predominantly affects young women. A loss of immunologic tolerance during SLE leads to the production of autoantibodies, of which antidouble-stranded DNA (dsDNA) is the most common and is specific for the disease. Autoantibody production facilitates the formation of immune complexes that deposit in tissues and promote local inflammation and injury, with the kidneys being most commonly affected. Numerous inflammatory cytokines are implicated in the pathophysiology of SLE, including TNF-␣. 9,10 TNF-␣ expression is increased in kidney biopsies, 11 and the prevalence of hypertension is elevated in patients with SLE, reaching as high as 75%, depending on the cohort. [12][13][14][15] These data suggest that SLE may be an important disease model to examine the mechanistic role of renal TNF-␣ in the development of hypertension.In the present study, we hypothesize that TNF-␣ is an important mediator of hypertension during the chronic in-

Role of the TNF pathway in the progression of diabetic nephropathy in KK-Aymice

“…Consistent with our present findings, Venegas et al (48) reported that ETN suppresses a downstream signaling of target of TNF-␣, such as NF-B in the renal cortex, although ETN did not affect the expression of membrane TNF-␣ in a mouse model of systemic lupus erythematosus. This lack of drug effect might be attributable to the following characteristics of ETN.…”

“…This lack of drug effect might be attributable to the following characteristics of ETN. First, ETN predominantly binds to circulating (soluble) TNF-␣ and does not affect the expression of membrane TNF-␣ in the kidney (48). Second, the binding of ETN (a diametric molecule) to membrane TNF-␣ is not as strong as that of infliximab (a trimeric molecule) due to the differences in structure, raising the possibility that ETN causes a decrease in TNF-␣ activity but that the effect is not strong enough to decrease membrane TNF-␣ expression in the kidney (44).…”

“…The experimental protocol was terminated when mice reached 16 wk of age. The dose of ETN was considered to be effective for the inhibition of TNF-␣ based on previous studies in mice (23,48). All mice were maintained in the same room under conventional conditions with a regular 12:12-h light-dark cycle and were temperature controlled at 24 Ϯ 1°C.…”

IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis by Inducing Expression of Linear Ubiquitin Chain Assembly Complex

“…We have observed that the amount of TNF-a is reduced by IFN-g treatment in the skin of cpdm mice. To confirm the involvement of TNF-a in cpdm, we treated cpdm mice with etanercept, which blocks the effect of TNF-a (37,38). Etanercept treatment ameliorated cpdm and inhibited keratinocyte apoptosis and infiltration of inflammatory cells such as granulocytes, macrophages, and mast cells (Supplemental Fig.…”

Tumor necrosis factor-α: regulation of renal function and blood pressure

“…These data seem to indicate that TNF-␣ mediates ANG II-dependent increases in blood pressure. Similarly, in a mouse model of lupus erythematosus etanercept infusion for 4 wk reduced blood pressure, albuminuria, glomerulosclerosis, and NF-B activity, suggesting that TNF-␣ causes inflammation and mediates the increase in blood pressure (152).…”