-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...

August 3, 2006; doi:10.1152/ajpregu.00168.2006.-Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that predominantly affects women during their reproductive years. Although women with SLE have hypertension, the underlying mechanisms for this have not been examined. Despite the fact that inflammation is associated with altered endothelial and vascular function, the role of altered vascular function in the development of hypertension during SLE is unclear. In the present study, we tested whether a mouse model of SLE (NZBWF1) develops hypertension and examined whether increased blood pressure was associated with impaired endothelial-dependent relaxation. Female NZBWF1 mice were studied at 8, 20, and 36 wk of age. By 36 wk, urinary albumin and antinuclear antibodies were increased in SLE compared with control mice. Mean arterial pressure, measured by radiotelemetry, was significantly increased in SLE mice (124 Ϯ 4 mmHg, n ϭ 10) compared with control NZW/LacJ mice (111 Ϯ 3 mmHg, n ϭ 7) at 36 wk. Isolated carotid arteries from NZBWF1 mice, precontracted with U-46619 for assessment of endothelialdependent relaxation, demonstrated a progressively impaired relaxation to ACh with age, although endothelial nitric oxide synthase mRNA expression was not different. Maximal tension generated by 5-hydroxytryptamine was increased in carotid arteries from NZBWF1 mice compared with controls at 8, 20, and 36 wk of age, suggesting a role for altered vascular function early on in the progression of SLE. Taken together, our data support a role for altered endothelial function as a contributing factor to the development of hypertension during SLE. systemic lupus erythematosus; autoimmune; hypertension; endothelial; pressure; auto-antibody SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) is a complex genetic autoimmune disorder that leads to the production of antibodies against an individual's own healthy tissues. Any organ system can be affected during SLE, although individuals often present with skin rashes, joint pain, and renal problems. While no known cure for SLE exists, current immunosuppressive therapies have markedly reduced shortterm mortality rates. Long-term mortality rates, on the other hand, are increasingly influenced by cardiovascular complications. Indeed, individuals with SLE are at an alarmingly high risk for stroke, myocardial infarction, atherosclerosis, renal disease, and hypertension.Interestingly, SLE predominantly affects women (at a ratio of 9:1 women-men) during reproductive years, a period when they are typically thought to be "protected" against the development of cardiovascular disease. During this time, women with SLE are Ͼ50 times more likely to develop cardiovascular disease independent of traditional Framingham risk factors (23), with a high prevalence of hypertension, atherosclerosis, and glomerulosclerosis (1,34,38). Despite the high incidence of hypertension and peripheral vascular disease, there have been few studies directed at understanding the mechanisms of hypertension during SL...

Abstract-Accumulating data indicate that metabolic syndrome is an inflammatory condition. Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with nephritis and cardiovascular disease. Evidence suggests that individuals with SLE are at risk for developing insulin resistance; however, this has not been directly examined. Using an established mouse strain with SLE (NZBWF1), we examined whether SLE is associated with increased body weight and fat deposition. Mean arterial pressure was significantly increased (140Ϯ4 versus 114Ϯ2 mm Hg; nՆ5) in SLE mice by 36 weeks of age compared with control mice (NZW/LacJ). Body weight in SLE mice was higher at each age compared with controls by 12%, 22%, and 34% (nϾ30). Visceral adipose tissue weight was increased in SLE by 44%, 74%, and 117% at 8, 20, and 36 weeks, respectively (nՆ12 etabolic syndrome can be characterized by a group of metabolic risk factors that includes central obesity, insulin resistance, dyslipidemia, increased blood pressure, and endothelial dysfunction. 1 Individuals with metabolic syndrome are at a markedly increased risk for developing hypertension and renal disease. Recent evidence indicates that inflammatory cytokines are elevated in patients with metabolic syndrome, 2-4 thus suggesting a role for chronic inflammation as an underlying mechanism for progression of this disease.Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder that predominantly affects women during their reproductive years. The presence of autoantibodies (typically antinuclear antibodies) is used diagnostically, and although SLE can influence many organ systems, the skin, joints, and kidneys are typically affected. Like metabolic syndrome, a large percentage of individuals with SLE are hypertensive. Evidence suggests that individuals with SLE are also at increased risk for developing insulin resistance 5 and changes in body mass composition 6 ; however, this has not been adequately examined.The purpose of the present study was to test whether the progression of SLE is associated with changes in body composition, insulin sensitivity, and other characteristics of the metabolic syndrome. To examine this, we used a genetic mouse model of SLE (NZBWF1) that exhibits many features of human SLE, including a complex genetic origin, a bias for the female sex, immune complex glomerulonephritis, and the presence of antinuclear antibodies. We reported recently that these mice have hypertension and impaired endothelialdependent relaxation. 7 The results of the present study show that NZBWF1 mice also have several other characteristics of the metabolic syndrome that may contribute to the hypertension, including central obesity, insulin resistance, and hyperleptinemia. These data show that the NZBWF1 strain may be an important model to study the effects of obesity and insulin resistance on SLE-associated hypertension. Methods AnimalsFemale NZBWF1 (SLE) and NZW/LacJ (control) obtained from Jackson Laboratories (Bar Harbor, ME) were maintained on a 12-hour light/d...

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One potential mechanism contributing to the increased risk for encephalopathies in women with preeclampsia is altered cerebral vascular autoregulation resulting from impaired myogenic tone. Whether placental ischemia, a commonly proposed initiator of preeclampsia, alters cerebral vascular function is unknown. This study tested the hypothesis that placental ischemia in pregnant rats (induced by reducing uterine perfusion pressure, RUPP) leads to impaired myogenic responses in middle cerebral arteries (MCA). Mean arterial pressure (in mmHg) was increased by RUPP (135±3) compared with normal pregnant rats (NP, 103±2) and non-pregnant controls (Ctrl, 116±1). MCA from rats sacrificed on gestation day 19 were assessed in a pressure ateriograph under active (+ Ca2+) and passive (0 Ca2+) conditions while luminal pressure was varied between 25 and 150 mmHg. The slope of the relationship between tone and pressure in the MCA was 0.08±0.01 in CTRL rats and was similar in NP rats (0.05±0.01). In the RUPP model of placental ischemia, this relationship was markedly reduced (slope = 0.01±0.00, p<0.05). Endothelial dependent and independent dilation was not different between groups nor was there evidence of vascular remodeling assessed by the wall:lumen ratio and calculated wall stress. The impaired myogenic response associated with brain edema measured by % water content (RUPP p<0.05 vs. CTRL and NP). This study demonstrates that placental ischemia in pregnant rats leads to impaired myogenic tone in the MCA and that the RUPP model is a potentially important tool to examine mechanisms leading to encephalopathy during preeclamptic pregnancies.