Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system (RAS) is a strong candidate as a mediator for the development and progression of lupus nephritis (LN). We performed an ethnically stratified analysis of 642 systemic lupus erythematosus (SLE) patients to determine whether various functional RAS gene polymorphisms are associated with SLE renal outcomes. Patients were genotyped for two angiotensin-converting enzyme (ACE) gene polymorphisms: Alu insertion/deletion (I/D) and 23 949 (CT)(2/3), and for two angiotensinogen (Atg) gene polymorphisms: M235T and C-532T. Multivariate analyses demonstrated associations between the ACE I/D, ACE (CT)(2/3) and Atg C-532T functional polymorphisms and LN among Asians. In stratified analyses among LN cases according to high vs low glomerular filtration rate (GFR), associations remained significant for the ACE D (odds ratio (OR) 5.9, P=0.001) and (CT)(2) (OR 6.2, P=0.001) alleles among Asian subjects with low GFR. Lastly, we found allelic dose-dependent associations between the ACE I/D (P=0.003), ACE (CT)(2/3) (P=0.005) and Atg M235T (P=0.04) polymorphisms, and GFR analyzed as a continuous variable among Asians. These findings suggest a significant role for ACE and Atg gene sequence variation and severity of LN among Asians with SLE.
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PMID:Renin-angiotensin system gene polymorphisms predict the progression to renal insufficiency among Asians with lupus nephritis. 1578 57

Recent immunosuppressive treatments for lupus nephritis have improved renal survival rate, however, there still exists lupus nephritis refractory to these treatments. Angiotensin receptor blockers (ARBs) are known not only to decrease blood pressure but also to have an independent renoprotecting effect by interrupting renin-angiotensin system. The aim of this study was to evaluate whether ARBs have an additive effect on refractory lupus nephritis. Enrolled in this trial were twelve patients with lupus nephritis who were diagnosed by renal biopsy and remained proteinuria despite corticosteroids and/or immunosuppressive treatments. ARB, losartan or candesartan, was administered for six months. Various clinical parameters were compared before and after ARB administration. Proteinuria decreased after ARB treatment in 83% of the patients and the median amount of proteinuria significantly decreased from 2530 mg/g Cr to 459 mg/g Cr (P = 0.03). In addition, serum albumin and cholesterol levels were significantly improved. Systolic blood pressure significantly decreased, but none had symptoms of hypotension. The antiproteinuric effect of ARB did not correlate with the reduction of blood pressure. Interestingly, higher total complement activity levels before ARB treatment were associated with a greater reduction of proteinuria. The addition of ARB would be a safe and effective treatment for lupus nephritis with persistent proteinuria despite corticosteroids and/or immunosuppressive treatments.
Lupus 2005
PMID:Antiproteinuric effect of ARB in lupus nephritis patients with persistent proteinuria despite immunosuppressive therapy. 1586 15

Genetic polymorphisms of the renin-angiotensin system (RAS) has been associated with cardiovascular events and the progression of nephropathy in several diseases. The objective of this study was to evaluate a possible association of the genetic polymorphisms of RAS with the development and/or progression of lupus nephritis in a Brazilian population. Seventy-five SLE patients with lupus nephropathy (LN group) were compared to 72 SLE patients without LN (SLE group) and 65 healthy individuals (CONTROL group), of sex and ethnic matched, in a Brazilian population sample. Mean global follow-up was 9 +/- 6 years for lupus without nephropathy and 11 +/- 7 years for lupus nephropathy. Following the extraction of genomic DNA from the leukocytes in the peripheral blood, angiotensin converting enzyme (ACE I/D), angiotensinogen (AGT M(235)T) and angiotensin II type 1 receptor (AGTR1 A(1166)C) genotypes were determined by the polymerase chain reaction. No significant difference of ACE, AGT and AGTR1 genotypes distribution between groups was observed in this study. There was no significant association between the variables of the RAS genotypes and the presence of hypertension in SLE. However, an increased frequency ofDD genotype (ACE I/D) was observed in SLE patients with LN who progressed to CRF compared to healthy controls (DD 60%, DI 26.7%, II 13.3% versus 27.7%, 60% and 12.3%, respectively; chi2 = 6.299, P = 0.0429). In the population studied, there was no influence of the RAS genetic polymorphisms in the development of lupus nephropathy, but the progression to CRF was associated with ACE DD polymorphism.
Lupus 2005
PMID:Polymorphisms of the renin-angiotensin system genes in Brazilian patients with lupus nephropathy. 1593 35

Patients with systemic lupus erythematosus (SLE) are known to have lower heart rate variability and impaired vagal modulation, and right lateral position has been shown to lead to a higher vagal modulation than supine position in healthy subjects and patients with cardiovascular diseases. This study evaluated the effect of disease activity and different recumbent positions on cardiac autonomic nervous modulation by heart rate variability analysis in patients with SLE. Thirty-five female patients with SLE and 33 female controls were enrolled in this study. Electrocardiogram was recorded during supine, left lateral, and right lateral positions for 15 min. Both time and frequency domains heart rate variability measures were calculated. The normalized high-frequency power was used as the index of vagal activity, and the low-/high-frequency power ratio as the index of sympathovagal balance. We found that patients with SLE had lower indices of time domain heart rate variability measures and lower low-frequency power, high-frequency power, and normalized high-frequency power than control subjects. SLE patients with lower serum albumin had lower normalized high-frequency power and higher low-/high-frequency power ratio. In patients with SLE, right lateral position could lead to higher high-frequency power, normalized high-frequency power, and lower low-/high-frequency power ratio than supine position. In addition, the lower the normalized high-frequency power in supine position the patient had, the greater the increase in normalized high-frequency power when the position of the patient was changed from supine to right lateral. Thus, serum albumin level might be used as a potential disease severity index of SLE, and right lateral position can lead to higher vagal modulation and lower sympathetic modulation, renin-angiotensin-aldosterone modulation, and vagal withdrawal than supine position in patients with SLE. Right lateral position can be used as an efficient and physiological vagal enhancer in SLE patients with depressed vagal modulation.
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PMID:Effect of disease activity and position on autonomic nervous modulation in patients with systemic lupus erythematosus. 1794 Jul 21

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that predominantly affects women during their reproductive years. Although SLE can affect any organ system, the kidneys are prominently involved in the form of immune complex glomerulonephritis. In addition, in women with SLE, risk for the development of cardiovascular disease is dramatically increased. Hypertension is a major risk factor for cardiovascular disease and is highly prevalent in women with SLE. Nevertheless, there has been little exploration of the pathophysiological mechanisms that promote SLE hypertension. This review discusses the role of several mechanisms, with an emphasis on the kidney, in SLE hypertension. These mechanisms include the renin-angiotensin system, endothelin, oxidative stress, sex steroids, metabolic changes, peroxisome proliferator-activated receptor-gamma, and, perhaps most importantly, chronic inflammation and cytokines. Growing evidence suggests a link between chronic inflammation and hypertension. Therefore, elucidation of mechanisms that promote SLE hypertension may be of significant value not only for patients with SLE, but also for a better understanding of the basis for essential hypertension.
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PMID:The pathophysiology of hypertension in systemic lupus erythematosus. 1915 8

Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT1) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT1A-deficient lpr mice, and they showed evidence of exaggerated AT1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT1A-deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.
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PMID:Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis. 1928 96

Renal disease is a major cause of mortality and morbidity in systemic lupus erythematosus. Among the histological classes of lupus nephritis, membranous nephropathy comprises only one-fifth of all cases. Reported survival and rates of end-stage renal disease in membranous lupus nephropathy (MLN) vary considerably, because of substantial heterogeneity among the published studies. The risk of progression from MLN to renal failure is generally reduced in the absence of proliferative lesions, but patients are, nevertheless, at risk of thromboembolic complications. The optimal therapy for MLN remains elusive because of a lack of controlled trials; however, cardiovascular protection and blockade of the renin-angiotensin system should be instituted early in all patients. Mixed membranous and proliferative lupus nephritis should be treated in the same way as pure proliferative lupus nephritis. If MLN is not accompanied by proliferative lesions but is associated with clinically relevant proteinuria, renal insufficiency or failure to respond to supportive therapies, immunosuppressive treatment is indicated. Treatment options include glucocorticoids combined with azathioprine, calcineurin inhibitors or alkylating agents. The efficacy of mycophenolate mofetil in MLN remains to be confirmed. Controlled trials to compare existing immunosuppressive agents and experimental modalities such as sirolimus, rituximab and infliximab should be undertaken in the future.
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PMID:Membranous nephropathy in systemic lupus erythematosus: a therapeutic enigma. 1932 86

To identify potential biomarkers in immune-mediated nephritis, urine from mice subjected to an augmented passive model of anti-glomerular basement membrane (GBM)-induced experimental nephritis was resolved using two-dimensional gels. The urinary proteome in these diseased mice was comprised of at least 71 different proteins. Using orthogonal assays, several of these molecules, including serum amyloid P (SAP), PG D synthase, superoxide dismutase, renin, and total protease were validated to be elevated in the urine and kidneys of mice during anti-GBM disease, as well as in mice with spontaneously arising lupus nephritis. Among these, urinary protease was the only marker that appeared to be exclusively renal in origin, whereas the others were partly serum-derived. Longitudinal studies in murine lupus demonstrated that total urinary protease had better predictive value for histologically active nephritis (r = 0.78) compared with proteinuria (r = -0.04), azotemia (r = 0.28), or the other markers examined, whereas urine SAP emerged as the single most predictive marker of histological glomerulonephritis. Collectively, these studies uncover total urinary protease, PG D synthase, SAP, and superoxide dismutase as novel biomarkers of anti-GBM disease and lupus nephritis, with stronger correlation to renal disease compared with currently employed biomarkers. These findings could have important diagnostic and prognostic ramifications in the management of these renal diatheses.
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PMID:Urine proteome scans uncover total urinary protease, prostaglandin D synthase, serum amyloid P, and superoxide dismutase as potential markers of lupus nephritis. 2006 16

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE), which is associated with significant morbidity and mortality. Renal involvement in SLE is heterogeneous; therefore, the treatment of LN is determined by the pathological type of LN and ranges from nonspecific measures such as maintenance of adequate blood pressure control and blockade of renin-angiotensin-aldosterone system to the use of immunosuppressive medications. Cyclophosphamide in combination with prednisone has been the standard of care for the treatment of proliferative forms of LN. However, the high rates of progression to end-stage renal disease coupled with adverse side effects from cyclophosphamide and prednisone administration have lead to an intensive search for more effective and less toxic therapies for LN. The authors review available treatment options for proliferative and membranous LN and summarize the results of recently published clinical trials that add new perspectives to the management of kidney disease in SLE.
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PMID:Treatment of proliferative and membranous lupus nephritis: review of key clinical trials. 2168 86

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.
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PMID:Blood pressure and renal hemodynamic responses to acute angiotensin II infusion are enhanced in a female mouse model of systemic lupus erythematosus. 2190 Jun 45


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