Early Lupus Nephritis Research Articles

Role of circulating miRNA-130b-3p and TGF-β 1cytokine in patients with systemic lupus erythematosus

BackgroundMicroRNAs (miRNAs) a single-stranded “noncoding” RNAs that regulate gene expression post transcriptionally and they were shown to play a role in the pathophysiology of lupus. MiR-130b-3p, which targets ERBIN (Erbb2 Interacting Protein), has been demonstrated to aid the epithelial to mesenchymal transition (EMT) in renal tubular epithelial cells. MiR-130b-3p is also identified as negative regulator of transforming growth factor-b1 (TGF-β1)-induced signaling pathway. This study aimed to investigate whether MiR-130b-3p is involved in the pathogenesis of lupus and to explore the correlation between MiR-130b-3p with TGF-β 1cytokine in patients with SLE. MethodsThe study was conducted in a total of 70 individuals which include 35 SLE patients and 35 healthy controls, The serum level of MiR-130b-3p were determined by two-step reverse transcription polymerase chain reaction (RT-PCR) and TGF-β1 levels were estimated by ELISA. ResultsThe MiR-130b-3p gene expression was increased (1.6-fold change) among SLE patients compared to controls, the difference was not statistically significant (p < 0.05). There was also a statistically significant increase in TGF-B1 serum levels (p < 0.001) in SLE patients compared to controls, however, a non-statistically significant difference between the SLE disease activity severity, anti-dsDNA antibodies positivity, and renal affection with the MiR-130b-3p gene expression (p < 0.01) and TGF-β1 level (p < 0.01) in this study. ConclusionThe results of the current study indicates that the serum levels of MiR-130b-3p and TGF-β1 are associated with pathogenesis of SLE and might be used as biomarker for the diagnosis of early lupus nephritis in SLE.

Comparison of clinical features and outcomes between patients with early and delayed lupus nephritis

BackgroundLupus nephritis is associated with increased risk of end-stage renal disease (ESRD) and all-cause mortality. We evaluated the clinical features and outcomes of patients with early and delayed lupus nephritis.MethodsThe medical records of 171 patients who met the 1997 revised classification criteria for systemic lupus erythematosus (SLE) with pathologic confirmation of lupus nephritis were reviewed. Early lupus nephritis was defined when lupus nephritis was histopathologically confirmed as the first clinical manifestation of SLE, whereas delayed lupus nephritis was defined as lupus nephritis that was identified after the diagnosis of SLE. Clinical and laboratory data, as well as kidney histopathology and medication usage were investigated. Kaplan-Meier and Cox-proportional hazard analysis was performed to compare the outcomes of early and delayed lupus nephritis and evaluate factors associated with ESRD and all-cause mortality.ResultsPatients with early lupus nephritis had higher disease activity (median non-renal SLE disease activity index-2000, 6.0 vs. 4.0; p < 0.001) and more frequent skin rash, oral ulcer and serositis; however, the proportion of patients with higher renal chronicity index was greater in the delayed lupus nephritis group (p = 0.007). Nevertheless, no difference was found regarding ESRD and all-cause mortality between the groups. In Cox-proportional hazard analysis, C-reactive protein level, creatinine level and chronicity index were factors associated with ESRD, while age and haemoglobin level were associated with all-cause mortality.ConclusionsIn conclusion, clinical outcomes of early and delayed lupus nephritis are not significantly different. Rigorous adherence to current treatment recommendations is essential for the treatment of lupus nephritis.

Up-regulation of Serum MiR-130b-3p Level is Associated with Renal Damage in Early Lupus Nephritis.

Systemic lupus erythematosus (SLE) is a common but severe autoimmune systemic inflammatory disease. Lupus nephritis (LN) is a serious complication of SLE,affecting up to 70% of SLE patients. Circulating microRNAs (miRNA) are emerging as biomarkers for pathological conditions and play significant roles in intercellular communication. In present research, serum samples from healthy control, early and late stage LN patients were used to analyze the expression profile of miRNAs by microarray. Subsequent study demonstrated that miR-130b-3p in serum of patients with early stage LN were significantly up-regulated when compared with healthy controls. In addition,we have also observed that the expression of a large amount of circulating microRNAs significantly decreased in patients with late stage LN. The further analysis found that the expression of serum miR-130b-3p was positively correlated with 24-hour proteinuria and renal chronicity index in patients with early stage LN.Transfection of renal tubular cellline(HK-2)with miR-130b-3p mimics can promote epithelial-mesenchymal transition (EMT). The opposite effects were observed when transfected with miR-130b-3p inhibitors. MiR-130b-3p negatively regulated ERBB2IP expression by directly targeting the 3′-UTR of ERBB2IP The circulating miR-130b-3p might serve as a biomarker and play an important role in renal damage in early stage LN patients.

Plasma concentrations of growth arrest specific protein 6 and the soluble form of its tyrosine kinase receptor Axl in patients with Systemic lupus erythematosus and Behçets disease

The aim of the present study was to investigate plasma concentrations of Gas6 and its soluble tyrosine kinase receptor sAxl in Systemic lupus erythematosus (SLE) and Behçets disease (BD) patients and to correlate those levels with clinical and laboratory manifestations of the diseases. The study included 89 female SLE and 49 male BD patients. Twenty-seven age and sex matched healthy volunteers served as controls. All patients were subjected to full clinical examination, laboratory investigations and assessment of disease activity. Plasma concentrations of Gas6 and sAxl were quantified using ELISA technique. The level of Gas6 and Axl were significantly altered in the SLE patients (p < 0.001) and in the BD patients (p 0.001 and 0.04 respectively) compared to those of the control. In SLE, the Gas6 was remarkably lower in those with class 1 lupus nephritis and in those with neuropsychiatric manifestations. In the BD patients, the level of Axl was significantly increased in those with neurological disease activity. The number of lymphocytes significantly negatively correlated with the gas6 and Axl levels significantly correlated with the number of neutrophils and negatively with the lymphocytic count in the BD patients. The plasma concentrations of Gas6 and Axl were significantly altered in SLE and BD patients, suggesting that the Axl receptor shedding is an active process affected by and influences Gas6-mediated Axl-signaling in both diseases. Special attention is required in SLE patients with early lupus nephritis and neuropsychiatric manifestations and BD patients presenting with neurological disease activity. The relation with lymphocytes and neutrophils in BD throws light on the role of gas6 and Axl on their known resistance to cell death. Although the mechanisms responsible for the initiation of BD remain to be clarified, the role of the apoptotic process seems critical throughout the disease.

4SC-101, A Novel Small Molecule Dihydroorotate Dehydrogenase Inhibitor, Suppresses Systemic Lupus Erythematosus in MRL-(Fas)lpr Mice

Immunosuppressive treatments of systemic lupus (SLE) remain associated with significant toxicities; hence, compounds with better toxicity profiles are needed. Dihydroorotate dehydrogenase (DHODH) inhibition with leflunomide has proven to be effective in autoimmune diseases including SLE, but leflunomide can cause a variety of side effects. We hypothesized that 4SC-101, a novel DHODH inhibitor with a more favorable toxicity profile, would be as effective as high-dose cyclophosphamide (CYC) in controlling experimental SLE of female MRL(Fas)lpr mice. Daily oral gavage of 30, 100, and 300 mg/kg 4SC-101 from 12 to 22 weeks of age was compared with either vehicle or CYC treatment (30 mg/kg/week, i.p.) in terms of efficacy and toxicity. Three hundred milligrams per kilogram 4SC-101 was as effective as CYC in depleting spleen autoreactive T cells, B cells, and plasma cells as well as the respective DNA and RNA serum autoantibodies. This was associated with a comparable amelioration of the renal, dermal, and pulmonary SLE manifestations of MRL(Fas)lpr mice. However, even the highest dose of 4SC-101 had no effect on bone marrow neutrophil counts, which were significantly reduced in CYC-treated mice. Together, the novel DHODH inhibitor 4SC-101 is as effective as high dose CYC in controlling SLE without causing myelosuppression. Hence, DHODH inhibition with 4SC-101 might be suitable to treat active SLE with fewer side effects than CYC.

Nucleosome Effects on Mesangial Cell Matrix and Proliferation: A Possible Role in Early Lupus Nephritis

Background: Oligonucleosomes (ON) have been demonstrated in the circulation and biopsies of lupus nephritis patients. Their presence as immune complexes is an early and persistent finding in lupus nephritis as are changes in mesangial matrix. Since ON competitively bind to glomerular mesangial cells (MC) in a receptor-like fashion, the purpose of our study was to investigate what effects ON have on MC matrix and proliferation. Methods: Rat and mouse MCs grown with ON or DNA for 1 week were dissociated from their matrices with Triton-X and their proteins were determined. MC collagen production, using collagenase sensitive ³H-proline incorporation, was measured after 48-hour incubation with ON and DNA. Similar experiments using 10-fold excess DNA were done to assess its blocking effect on ON induced collagen synthesis. ON interaction with matrix was evaluated by incubated ¹²⁵I-ON with MC matrix grown with ON or media alone for 1 week. Results: MCs stimulated by ON but not DNA significantly increased total matrix protein, total collagen and specifically, collagen type I synthesis. DNA inhibited ON-stimulated collagen synthesis. MC matrix incubated with ON binds 3 times more ¹²⁵I-ON than matrix generated in media alone. Histone, a major component of nucleosomes, significantly increased ³H-thymidine incorporation. Conclusions: Oligonucleosomes, both qualitatively and quantitatively, influence mesangial cell function. These findings for the first time suggest ON to be pathogenic independent of their IC construct. DNA inhibition of ON induced mesangial matrix changes suggests participation of the ON/DNA receptor. Increased production of collagen type I may contribute to glomerulosclerosis.

The significance of arterial hypertension at the onset of clinical lupus nephritis.

The prognostic importance of hypertension at the onset of clinical lupus nephritis is not well established. We studied retrospectively 44 patients with lupus nephritis in order to ascertain the prevalence...

Mechanism of Localization of Immune Complexes in NZB/W Mice with Early Nephritis

We investigated the pathogenesis of mesangial proliferative lupus nephritis in NZB/W mice under conditions that allowed us to examine removal of immune complexes from the circulation, uptake by the mononuclear phagocyte system, and localization in kidney tissue. These studies were performed at a time when variables such as the quantity of endogenous immune complexes, complement concentration, and carrier state of blood cells (platelets) were controlled. NZB/W mice and C57BL/6 (control) mice showed comparable kinetics for removal of a subsaturating dose of immune complexes (2.5 mg bovine serum albumin-antibovine serum albumin) from the circulation; additionally, the liver uptake and kidney localization of these immune complexes were comparable between NZB/W and control mice. The localization of immune complexes in the glomerular mesangium of NZB/W mice could not be attributed to enhanced production of endogenous immune complexes, to decreased removal of immune complexes from the circulation, to impaired uptake by the liver, or to complement concentration and carrier state of blood cells. It appears, by exclusion, that mesangial deposits of immunoreactants in early lupus nephritis may result from interaction of antibodies with antigens in mesangia.

Activities of a Soluble Extract from Lymphoid Cells of MRL Mice

Soluble extract (sEx) was prepared from lymphoid cells of MRL/Mp-lpr/lpr(MRL/l) mice with early lupus nephritis and also of MRL/Mp-+/+ (MRL/n) mice. sEx from lymph node and spleen T cells of MRL/l mice had an activity for B cells to differentiate into immunoglobulin-producing cells but that of MRL/n mice did not show such an activity. sEx of MRL/l mice also enhanced the in vitro response of B cells to a suboptimal dose of lipopolysaccharide. Implication of these phenomena in the development of lupus nephritis is discussed.

Significance of urinary gamma globulin in lupus nephritis. I. Electrophoretic analysis.

LABORATORY methods for the detection of early renal involvement in patients with systemic lupus erythematosus are not satisfactory. Pathologic changes of early lupus nephritis have been found in kidney biopsies from patients who have a normal urinary sediment, even when an Addis count is performed. Moreover, proteinuria may be so minimal initially that it escapes detection by routine testing of the random specimen. Two areas of investigation suggested the possibility that an increase in urinary gamma globulin can be anticipated in the early active stage of lupus nephritis. In the first place, there is evidence from light and electron microscopy . . .