Hypertension in an experimental model of systemic lupus erythematosus occurs independently of the renal nerves

Mathis, Keisa W.; Venegas-Pont, Marcia; Flynn, Elizabeth R.; Maric‐Bilkan, Christine; Dwyer, Terry; Ryan, Michael J.

doi:10.1152/ajpregu.00602.2012

Cited by 34 publications

(44 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Female NZBWF1 mice represent a long established model of SLE with immune complex mediated glomerulonephritis; therefore, it is unlikely that the development of albuminuria is strictly related to the hypertension. In support of this, we recently published work showing that bilateral renal denervation in this model ameliorates albuminuria independently of changes in blood pressure (51). In addition, studies in the NZBWF1 model show that lowering blood pressure alone is not sufficient to reduce renal injury (52).…”

Section: Discussionmentioning

confidence: 55%

17β-Estradiol Protects Against the Progression of Hypertension During Adulthood in a Mouse Model of Systemic Lupus Erythematosus

2014

Self Cite

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with a high prevalence of hypertension and cardiovascular disease. Because SLE predominantly affects women, estrogen is commonly implicated as a contributor to SLE disease progression. Utilizing an established mouse model of SLE (female NZBWF1) we tested whether estrogen has a causal role in the development of hypertension in adulthood. Thirty-week-old SLE and control mice (NZW/LacJ) underwent either a sham or ovariectomy (OVX) procedure. 17β-estradiol (E2; 5μg/mouse, twice/week, s.c.) was administered to a subset of OVX mice. Mean arterial pressure (in mmHg) was increased in SLE mice (134±4 versus 119±3 in controls). Contrary to our hypothesis, OVX exacerbated the hypertension in female SLE mice (153±3; p<0.05 vs. SLE sham), and repletion of E2 prevented the OVX induced increase in blood pressure (132±2). The prevalence of albuminuria was increased in SLE mice in comparison to controls (37% vs. 0%). OVX increased the prevalence in SLE mice (70% versus 37% in SLE shams). Repletion of E2 completely prevented albuminuria in OVX SLE mice. Renal cortical TNF-α was increased in SLE mice compared to controls and was further increased in OVX SLE. The OVX induced increase in renal TNF-α expression was prevented by repletion of E2. Treatment of OVX SLE mice with the TNF-α inhibitor, etanercept, blunted the OVX induced increase in blood pressure (140±2) and prevalence of albuminuria (22%). These data suggest that 17β-estradiol protects against the progression of hypertension during adulthood in SLE, in part, by reducing TNF-α.

show abstract

Section: Discussionmentioning

confidence: 55%

17β-Estradiol Protects Against the Progression of Hypertension During Adulthood in a Mouse Model of Systemic Lupus Erythematosus

2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Without longitudinal assessment of blood pressure, the question of whether the increase in blood pressure precedes the development of albuminuria arises. However, based on our previously published work showing that blood pressure and albuminuria are not necessarily associated (12,29), we are confident this is not the case.…”

Section: Impact Of Early Life Ovx On Blood Pressure In Adulthood Durimentioning

confidence: 75%

Impact of early life ovariectomy on blood pressure and body composition in a female mouse model of systemic lupus erythematosus

Gilbert

Ryan

2014

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

Because of the preponderance of women affected by the chronic autoimmune disease systemic lupus erythematosus (SLE), estrogen is thought to contribute to SLE disease progression. This is supported by evidence from experimental animal models of SLE showing that removal of estrogen in young female mice delays autoantibody production and renal injury and lengthens survival. Blood pressure and changes in body composition are important cardiovascular risk factors that can be regulated by estrogens. Because cardiovascular disease is the leading cause of death in patients with SLE, we used an established female mouse model of SLE (NZBWF1) to test whether early life removal of estrogen impacts the development of hypertension and changes in body composition commonly associated with SLE. Eight-week-old female SLE and control mice (NZW/LacJ) underwent either a sham operation or ovariectomy. Body weight, body composition (fat and lean masses), and renal injury (albuminuria) were monitored until mice reached 34 wk of age, at which time mean arterial pressure was assessed in conscious animals by a carotid catheter. Early life removal of the ovaries delayed the onset of autoantibody production and albuminuria while causing an increase in body weight and fat mass. Blood pressure in the adult was not altered by early life removal of the ovaries. These data suggest that estrogens may have a permissive role for the development of SLE while helping to maintain normal body weight and composition, which is associated with reduced cardiovascular risk.

show abstract

“…Blood pressure was recorded at the end of the 14-week protocol in conscious freely-moving mice as previously reported by our laboratory 9,10,12,14 .…”

Section: Methodsmentioning

confidence: 99%

“…Plasma levels of anti-double-stranded DNA (dsDNA) antibodies, a clinical hallmark of SLE, were measured at week 34 as previously described 9,11,12,14 and are presented as a positive antibody activity index per the manufacturer's instructions and as previously published 15 . An antibody activity less than 1 is considered negative, whereas activity greater than 1 is considered positive.…”

Section: Methodsmentioning

confidence: 99%

Preventing Autoimmunity Protects Against the Development of Hypertension and Renal Injury

et al. 2014

Self Cite

View full text Add to dashboard Cite

Several studies suggest a link between autoimmunity and essential hypertension in humans. However, whether autoimmunity can drive the development of hypertension remains unclear. The autoimmune disease systemic lupus erythematosus is characterized by autoantibody production and the prevalence of hypertension is markedly increased in this patient population compared to normal healthy women. We hypothesized that preventing the development of autoimmunity would prevent the development of hypertension in a mouse model of lupus. Female lupus (NZBWF1) and control mice (NZW) were treated weekly with anti-CD20 or IgG antibodies (both 10 mg/kg, IV) starting at 20 weeks of age for 14 weeks. Anti-CD20 therapy markedly attenuated lupus disease progression as evidenced by reduced CD45R+ B cells and lower double-stranded DNA autoantibody activity. In addition, renal injury in the form of urinary albumin, glomerulosclerosis, and tubulointerstitial fibrosis, as well as tubular injury (indicated by renal cortical expression of neutrophil gelatinase-associated lipocalin) was prevented by anti-CD20 therapy in lupus mice. Finally, lupus mice treated with anti-CD20 antibody did not develop hypertension. The protection against the development of hypertension was associated with lower renal cortical tumor necrosis factor-α expression, a cytokine that has been previously reported by us to contribute to the hypertension in this model, as well as renal cortical monocyte chemoattractant protein -1 expression and circulating T cells. These data suggest that the development of autoimmunity and the resultant increase in renal inflammation is an important underlying factor in the prevalent hypertension that occurs during systemic lupus erythematosus.

show abstract

Hypertension in an experimental model of systemic lupus erythematosus occurs independently of the renal nerves

Cited by 34 publications

References 43 publications

17β-Estradiol Protects Against the Progression of Hypertension During Adulthood in a Mouse Model of Systemic Lupus Erythematosus

17β-Estradiol Protects Against the Progression of Hypertension During Adulthood in a Mouse Model of Systemic Lupus Erythematosus

Impact of early life ovariectomy on blood pressure and body composition in a female mouse model of systemic lupus erythematosus

Preventing Autoimmunity Protects Against the Development of Hypertension and Renal Injury

Contact Info

Product

Resources

About