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.

Several lines of evidence suggest that essential hypertension originates from an autoimmune-mediated mechanism. One consequence of chronic immune activation is the generation of oxygen-derived free radicals, resulting in oxidative stress. Renal oxidative stress has direct pro-hypertensive actions on renal microvascular and tubular function. Whether oxidative stress contributes to the prevalent hypertension associated with autoimmune disease is not clear. We previously showed that female NZBWF1 mice, an established model of the autoimmune disease systemic lupus erythematosus (SLE), develop hypertension associated with renal oxidative stress. In the present study we tested the hypothesis that oxidative stress contributes to autoimmune-mediated hypertension by treating SLE and control (NZW/LacJ) mice with tempol (2 mM) and apocynin (1.5 mM) in the drinking water for 4 weeks (T+A). Although the treatment did not alter SLE disease activity (assessed by plasma double-stranded DNA autoantibodies), blood pressure and renal injury (urinary albumin) were reduced in the treated SLE mice. T+A-treated SLE mice had reduced expression of nitrosylated proteins in the renal cortex, as well as reduced urinary and renal cortical hydrogen peroxide, suggesting that treatment reduced renal markers of oxidative stress. These data suggest that renal oxidative stress plays an important mechanistic role in the development of autoimmune-mediated hypertension.

Several isoforms of apolipoprotein J/clusterin (CLU) are encoded from a single gene located on chromosome 8 in humans. These isoforms are ubiquitously expressed in the tissues, and have been implicated in aging, neurodegenerative disorders, cancer progression, and metabolic/cardiovascular diseases including dyslipidemia, diabetes, atherosclerosis and myocardial infarction. The conventional secreted form of CLU (sCLU) is thought to be a component of high density lipoprotein-cholesterol. sCLU functions as a chaperone for misfolded proteins and it is thought to promote survival by reducing oxidative stress. Nuclear CLU, a truncated CLU formed by alternative splicing, is responsible for promoting apoptosis via a Bax-dependent pathway. There are putative regulatory sites in the promoter regions of CLU, which are occupied by transcription factors such as transforming growth factor (TGF)-β inhibitory element, activator protein-1, CLU-specific elements, and carbohydrate response element. However, the molecular mechanisms underlying the distinct roles of CLU in a variety of conditions remain unclear. Although the function of CLU in cancer or neurological disease has been studied intensively for three decades, physiological roles of CLU seem unexplored in the cardiovascular system and metabolic diseases. In this review, we will discuss general characteristics and regulations of CLU based on previous literature and assess the recent findings associated with its physiological roles in different tissues including the vasculature, heart, liver, kidney, adipose tissue, and brain.

Background: Alcohol abuse, both chronic and acute, is a known modulator of immune function and is associated with increased incidence of traumatic injury. Previously, we demonstrated that acute alcohol intoxication before hemorrhagic shock impairs hemodynamic and neuroendocrine counterregulation, suppresses early lung proinflammatory cytokine expression, and increases mortality from infection during recovery. In the present study, we examined the impact of a 3-day alcohol binge on host responses during trauma/hemorrhage (TÂHem) and following overnight recovery.Methods: Chronically catheterized, adult male Sprague-Dawley rats were administered an intragastric bolus of alcohol (5 g/kg; 30% w/v) or isocaloric dextrose solution for 3 consecutive days, followed by a 2.5 g/kg dose on day 4 before undergoing full-thickness muscle-crush and fixed pressure ($40 mmHg) hemorrhage and fluid resuscitation (2.4Âtotal blood volume removed).Results: Alcohol-binge produced a 16% decrease in basal mean arterial blood pressure (MABP), reduced the total blood loss required to reach and to sustain MABP of 40 mmHg, markedly blunted the increase in circulating epinephrine and norepinephrine (20-fold and 3-fold, respectively) levels, and increased immediate mortality from TÂHem. Consistent with our previous reports, significant up-regulation in lung and spleen tumor necrosis factor (TNF)-a and interleukin (IL)-1a expression was observed immediately following TÂHem and fluid resuscitation. Only the TÂHem-induced increase in lung TNF-a was prevented by binge alcohol administration. Following overnight recovery, significant lipopolysaccharide (LPS)-stimulated release of TNF-a, IL-1a, IL-6, and IL-10 was observed in cells isolated from blood and the alveolar and pleural compartments from all experimental groups. While TÂHem did not prevent LPS-induced release of TNF-a, IL-1a, IL-6, or IL-10 at 6 or 24 hours, alcohol binge suppressed TNF-a, IL-1 and IL-6 release, without altering IL-10 response in cells isolated from blood and pleural compartment. No significant modulation of alveolar macrophage response was observed following alcohol binge and TÂHem.Conclusions: These results indicate that a 3-day alcohol binge results in hemodynamic instability associated with attenuated neuroendocrine activation and increased mortality during TÂHem as well as sustained suppression of the proinflammatory cytokine response of blood and pleural-derived cells to a ''second-hit'' inflammatory challenge. As a result, we speculate that the net shift toward an antiinflammatory state may contribute to enhanced susceptibility to infection during the recovery period.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder with prevalent hypertension and renal injury. In this study, we tested whether the renal nerves contribute to the development of hypertension in an established mouse model of SLE (NZBWF1). Female SLE and control (NZW/LacJ) mice were subjected to either bilateral renal denervation or a sham procedure at 32 wk of age. Two weeks later, blood pressure was assessed in conscious mice using carotid artery catheters. Blood pressure was higher in SLE mice compared with controls, as previously reported; however, blood pressure was not altered in the denervated SLE or control mice. The development of albuminuria was markedly blunted in denervated SLE mice; however, glomerulosclerosis was increased. Renal denervation reduced renal cortical expression of monocyte-chemoattractant protein in SLE mice but did not significantly alter renal monocyte/macrophage infiltration. Renal cortical TNF-α expression was also increased in sham SLE mice, but this was not impacted by denervation. This study suggests that the renal nerves do not have a significant role in the pathogenesis of hypertension, but have a complex effect on the associated renal inflammation and renal injury.

Systemic lupus erythematosus (SLE) is a risk factor for hypertension. Previously, we demonstrated that an established mouse model of SLE (female NZBWF1 mice) develops hypertension with renal inflammation and oxidative stress, both characteristics known as contributing mechanisms to the development of salt-sensitive hypertension. On the basis of this model, we hypothesized that blood pressure in SLE mice would be salt-sensitive. Thirty-week-old female SLE and control mice (NZW/LacJ) were fed 8% high-salt (HS) diet or normal diet (0.4% salt) for 4 wk. Plasma levels of double-stranded DNA (dsDNA) autoantibodies, a marker of SLE disease activity, were increased in SLE mice compared with controls (472 ± 148 vs. 57 ± 17 U/ml × 1,000, P < 0.001). HS did not alter dsDNA autoantibody levels in SLE or control mice. Mean arterial pressure was increased in SLE mice compared with controls (132 ± 3 vs. 118 ± 2 mmHg, P < 0.001) and was not significantly altered by the HS diet in either group. Similarly, albuminuria was higher in SLE mice compared with controls (10.7 ± 9.0 vs. 0.3 ± 0.1 mg/day) but was not significantly increased in SLE or control mice fed a HS diet. In summary, blood pressure during SLE is not salt-sensitive, and the HS diet did not adversely affect SLE disease activity or significantly augment albuminuria. These data suggest that renal inflammation and oxidative stress, characteristics common to both SLE and models of salt-sensitive hypertension, may have diverging mechanistic roles in the development of hypertension.

-Inflammation and immune system dysfunction contributes to the development of cardiovascular and renal disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that carries a high risk for both renal and cardiovascular disease. While hemodynamic changes that may contribute to increased cardiovascular risk have been reported in humans and animal models of SLE, renal hemodynamics have not been widely studied. The renin-angiotensin system (RAS) plays a central role in renal hemodynamic control, and although RAS blockade is a common therapeutic strategy, the role of RAS in hemodynamic function during SLE is not clear. This study tested whether mean arterial pressure (MAP) and renal hemodynamic responses to acute infusions of ANG II in anesthetized animals were enhanced in an established female mouse model of SLE (NZBWF1). Baseline MAP was not different between anesthetized SLE and control (NZWLacJ) mice, while renal blood flow (RBF) was significantly lower in mice with SLE. SLE mice exhibited an enhanced pressor response and greater reduction in RBF after ANG II infusion. An acute infusion of the ANG II receptor blocker losartan increased RBF in control mice but not in mice with SLE. Renin and ANG II type 1 receptor expression was significantly lower, and ANG II type 2 receptor expression was increased in the renal cortex from SLE mice compared with controls. These data suggest that there are fewer ANG II receptors in the kidneys from mice with SLE but that the existing receptors exhibit an enhanced sensitivity to ANG II. inflammation; angiotensin receptor; autoimmune INFLAMMATION AND IMMUNE SYSTEM dysregulation are recognized as prominent contributors to the development and progression of cardiovascular and renal disease. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder associated with a high risk for the development of renal and cardiovascular disease, which are major causes of mortality in these patients (43). Almost all patients with SLE have at least some evidence of renal damage on biopsy (4, 11), and measures of declining renal function, including elevated serum creatinine and blood urea nitrogen or reduced filtration fraction, are commonly reported (11,20,28).The renin-angiotensin system (RAS) is well known for its critical role in renal hemodynamic control and blood pressure regulation and is a common therapeutic target in patients with SLE. Although renal dysfunction and blockade of the RAS system are common to patients with SLE, renal hemodynamic responses to ANG II have not been previously investigated. In the present study, we tested the hypothesis that during SLE, there is an enhanced renal hemodynamic response to acute infusion of ANG II. This hypothesis was tested using an experimental mouse model of SLE.The New Zealand Black/White F1 hybrid (NZBWF1) is an established and widely used model of lupus nephritis (8). Like humans with SLE, female NZBWF1 mice exhibit declining renal function with age (5, 23, 29, 42), and we previously reporte...

Recent evidence suggests hypertension may be secondary to chronic inflammation that results from hypoactive neuro-immune regulatory mechanisms. To further understand this association, we used systemic lupus erythematosus (SLE) as a model of inflammation-induced hypertension. In addition to prevalent inflammatory kidney disease and hypertension, SLE patients suffer from dysautonomia in the form of decreased efferent vagal tone. Based on this, the cholinergic anti-inflammatory pathway, an endogenous vagus-to-spleen mechanism that, when activated results in decreases in systemic inflammation, may be compromised in SLE. We hypothesized that stimulation of the cholinergic anti-inflammatory pathway via pharmacological potentiation of the efferent vagus nerve would reduce inflammation and halt the development of hypertension and renal injury in SLE. Female NZBWF1 mice, an established model of murine SLE, and female control mice were treated with galantamine (4 mg/kg daily ip), an acetylcholinesterase inhibitor, or saline for 14 days. At the end of therapy, carotid catheters were surgically implanted and were used to measure mean arterial pressure before the animals were euthanized. Chronic galantamine administration attenuated both splenic and renal cortical inflammation, which likely explains why the hypertension and renal injury (i.e., glomerulosclerosis and fibrosis) typically observed in murine SLE was attenuated following therapy. Based on this, the anti-inflammatory, antihypertensive, and renoprotective effects of galantamine may be mediated through activation of the cholinergic anti-inflammatory pathway. It is possible that dysfunction of the cholinergic anti-inflammatory pathway exists in SLE at the level of the efferent vagus nerve and promoting restoration of its activity through central cholinergic receptor activation may be beneficial.