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-

-Women with systemic lupus erythematosus (SLE) exhibit a high prevalence of hypertension and renal injury. Rosiglitazone (Rosi), a peroxisome proliferator activator receptor gamma (PPAR␥) agonist, has renal protective and antihypertensive effects. We tested whether Rosi ameliorates hypertension and renal injury in a female mouse model of SLE (NZBWF1). Thirty-week-old SLE and control (NZW/LacJ) mice (n Ն 6/group) were fed Rosi (5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in standard chow) or standard chow for 4 wk. SLE mice had increased blood pressure (BP in mmHg) compared with controls (139 Ϯ 4 vs. 111 Ϯ 4, P Ͻ 0.05). Rosi treatment lowered BP in SLE mice (127 Ϯ 4, P Ͻ 0.05) but not in controls (111 Ϯ 4). Urinary albumin (g/mg creatinine) was increased in SLE mice compared with controls (12,396 Ϯ 6,525 vs. 50 Ϯ 6) and reduced with Rosi treatment (148 Ϯ 117). Glomerulosclerosis (% of glomeruli with sclerosis) was reduced in Rosi-treated SLE mice (4.2 Ϯ 1.6 vs. 0.4 Ϯ 0.3, P Ͻ 0.05). Renal monocyte/ macrophage numbers (cell number/1,320 points counted) were reduced in SLE mice treated with Rosi (32.6 Ϯ 11.0 vs. 10.6 Ϯ 3.6, P Ͻ 0.05) but unchanged in controls (3.7 Ϯ 1.6 vs. 3.7 Ϯ 2.0). Renal osteopontin expression, a cytokine-regulating macrophage recruitment, was reduced in Rosi-treated SLE mice. Urinary endothelin (in pg/mg creatinine) was increased in SLE mice compared with controls (1.9 Ϯ 0.59 vs. 0.6 Ϯ 0.04, P Ͻ 0.05) and reduced in SLE mice treated with Rosi (0.8 Ϯ 0.11, P Ͻ 0.05). PPAR␥ protein expression in the renal cortex was significantly lower in SLE mice compared with controls and was unaffected by Rosi. These data suggest that Rosi may be an important therapeutic option for the treatment of SLE hypertension and renal injury. lupus; inflammation; endothelin; glomerulosclerosis; proliferator activated receptor gamma SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) is a chronic autoimmune inflammatory disorder that has a strong predilection for women during their reproductive years. The hallmark of the disease is the production of autoantibodies such as antinuclear antibodies, and more specifically anti-double-stranded DNA (antidsDNA) antibodies. Accumulating evidence indicates that the major cause of death among patients with SLE is cardiovascular disease (17,22,23,26). Indeed, studies have reported that women with SLE are at a 50-fold greater risk for developing cardiovascular disease independent of traditional Framingham Heart Study risk factors (35). One of the major factors contributing to the progression of cardiovascular disease is increased arterial pressure. Importantly, SLE is associated with a high incidence of hypertension (1, 41, 56).The kidneys are prominently affected during SLE in the form of immune complex glomerulonephritis. This occurs in greater than 50% of patients with SLE (18) and is caused, in part, by circulating anti-dsDNA antibody-mediated formation of immune complexes (51). Few advances have been made toward the treatment of SLE and the associated nephritis and hypertension in the past 40 years. Patients with SL...

Irreversible loss of high DeltaPsim in thawed oocytes may be associated with defects in Ca2+ signalling after insemination and could have downstream consequences for normal embryogenesis.

Flash photolysis of bis[4.5-di(methylsulfanyl) 1,3-dithiol-2-ylidene]-9,10(-dihydroanthracene (1) in chloroform leads to formation of the transient radical cation species 1.+ which has a diagnostic broad absorption band at lambdamax approximately 650 nm. This band decays to half its original intensity over a period of about 80 micros. Species 1.+ has also been characterised by resonance Raman spectroscopy. In degassed solution 1.+ disproportionates to give the dication 1(2+), whereas in aerated solutions the photodegradation product is the 10-[4,5-di(methylsulfanyl) 1,3-dithiol-2-ylidene]anthracene-9(10 H)one (2). The dication 1(2+) has been characterised by a spectroelectrochemical study [lambdamax (CH2Cl2) = 377, 392, 419, 479 nm] and by an X-ray crystal structure of the salt 1(2-) (ClO4)2, which was obtained by electrocrystallisation. The planar anthracene and 1,3-dithiolium rings in the dication form a dihedral angle of 77.2 degrees; this conformation is strikingly different from the saddle-shaped structure of neutral 1 reported previously.