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Lupus nephritis (LN) refers to renal involvement in systemic lupus erythematosus and is characterized by hematuria, proteinuria, edema, hypertension and renal insufficiency. The complete remission rate of proliferative LN remains low using the current induction protocols and LN tends to flare. Scientific and standardized diagnosis and therapy are crucial for the treatment of LN. Therefore, based on the current international and domestic experiences and guidelines, the Chinese Rheumatology Association developed the recommendations of diagnosis and therapy for LN, with the purpose of enhancing efficacy, reducing flare, halting renal progression and improving outcome of LN.
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Objective To study the role of JAK-STAT singal transduction pathway in the interstitial fibrosis of unilateral ureter obstruction (UUO)mice. Methods Mice UUO model was established and the phosphorylation of JAK-STAT was examined at day 1,4,7 and 14 after ligation of the ureter.Mice in the treatment group were treated with daily injection of selective JAK2 inhibitor AG490 starting 2 h before ureter ligation until sacrifice while vehicle alone was given to mice in the model control group.Mice were sacrificed at day 14 after the establishment of model.Renal tubular lesion and interstitial fibrosis were assessed on paraffin section.Immunohistochemistry was used to detect renal macrophage infihration and α-SMA expression.The expression of collagen Ⅲ and MCP-1 mRNA was measured by RT-PCR.Phosphorylation of JAK2and STAT1 was examined by Western blotting. Results JAK2-STAT1 signaling transduction pathway was activated in UUO model.The activation of JAK2-STAT1 was closely correlated with the progression of renal injury,tubular histological lesions and interstitial fibrosis.AG490 treatment significantly inhibited the phosphorylation of JAK2 and STAT1 (P＜0.01).AG490 treatment also significantly reduced tubular lesions[(21.7 ±1.7)% vs (49.4±1.0)%]and interstitial fibrosis(1.0±0.1 vs 2.3±0.2),α-SMA expression(0.9±0.1 vs 2.1±0.2)and maerophage accumulation[(13.3±1.6)cells/HPF vs (34.4±1.0)cells/HPF](all P＜0.01).In addition,AG490 significantly inhibited the expression of collagen Ⅲ and MCP-1 mRNA. Conclusion JAK-STAT signaling plays an important role in renal tubulointerstitial inflammation and fibrosis.
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Objective To assess the effects of early correction of anemia with recombinant human erythropoietin (rHuEPO) on the development and progression of left ventricular hypertrophy (LVH) in patients with mild-to-moderate chronic renal insufficiency (CRI) who are not on hemodialysis. Methods A total of 158 patients with serum creatinine from 147μmol/L to 400μmol/L were nrolled in this prospective, multicenter study. Eighty-six patients with hemoglobin (Hb)＜110g/L received rHuEPO treatment with a target Hb of ≥110g/L (Group A). Forty patients with comparable Hb concentration (＜110g/L) but did not receive rHuEPO (Group B) and 32 patients with Hb≥110g/L and without rHuEPO treatment (Group C) were served as controls. Left ventricular mass index (LVMI) was evaluated by echocardiography at baseline and every 3 months for 2 years. Results There was no difference in age, gender, etiology of renal failure, blood pressure and cardiovascular risk factors among the 3 groups. At baseline, the prevalence of LVH was 72.1% in group A,72.5% in group B and 59.4% in group C. LVMI was inversely correlated with Hb levels (r=0.70, P＜0.01). During the 2-year period, the mean LVMI decreased from 142.6±25.7g/m2 to 132.4±18.5 g/m2 in group A, while increased significantly in both group B and group C. The mean Hb concentration increased from 93.8±14.6g/L to 111.2±10.3g/L (P＜0.05) in group A, but tended to decrease in group B and group C. There was no significant change of the mean blood pressure, number of anti-hypertensive drugs and serum creatinine concentrations in all 3 groups. However, patients' serum creatinine doubled more often in group B and group C than in group A.Conclusions LVH was common in predialysis CRI patients and was associated with the severity of anemia. Early intervention with rHuEPO may reverse LVH in these patients.
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<p><b>OBJECTIVE</b>To investigate the role of IL-17 in the overproduction of autoantibodies and IL-6 overexpression by peripheral blood mononuclear cells (PBMC) of lupus nephritis (LN) patients.</p><p><b>METHODS</b>Fifteen consecutively hospitalized LN patients were selected as subjects and 15 healthy adults as normal controls. PBMC were obtained by Ficoll density gradient centrifugation. IgG, anti-dsDNA antibody and IL-6 protein levels were assessed using enzyme-linked immunosorbent assays (ELISA) on the supernatant of cultured PBMC of LN patients or normal controls. IL-6 mRNA levels in PBMC were measured using reverse transcription-polymerase chain reaction (RT-PCR).</p><p><b>RESULTS</b>In medium culture, IgG, anti-dsDNA and IL-6 protein levels of the supernatant of PBMC from LN patients were significantly higher than those from normal controls (1492.1 +/- 73.2 ng/ml vs 636.7 +/- 51.9 ng/ml for IgG, 306.6 +/- 53.7 IU/ml vs 95.8 +/- 11.6 IU/ml for anti-dsDNA and 50.92 +/- 15.92 ng/ml vs 1.77 +/- 0.73 ng/ml for IL-6, all P < 0.001). In LN patients, IgG, anti-dsDNA and IL-6 protein levels were higher in the supernatants of PBMC in the IL-17-stimulated culture than the medium culture, but in normal controls, only the IL-6 protein levels were significantly higher. The increase in IgG, anti-dsDNA and IL-6 protein levels induced by IL-17 was dose-dependent and could be completely blocked by IL-17 monoclonal antibody mIgG(28) and partially blocked by dexamethasone. Similarly, IL-6 mRNA overexpression of PBMC in LN patients or normal controls induced by IL-17 was both dose- and time-dependent. During medium culture, IL-6 mRNA levels in LN patients were significantly higher than those in normal controls (1.80 +/- 0.11 vs 0.36 +/- 0.07). During stimulation with IL-17, IL-6 mRNA levels in LN patients were higher than those in normal controls (3.21 +/- 0.24 vs 1.30 +/- 0.14, P < 0.05) and also significantly higher when comparing the stimulated culture with the medium culture either in LN patients or normal control.</p><p><b>CONCLUSIONS</b>IL-17 may play an important role in the pathogenesis of LN through the induction of IgG, anti-dsDNA overproduction and IL-6 overexpression of PBMC in LN patients.</p>
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Adolescent , Adult , Female , Humans , Male , Antibodies, Antinuclear , Autoantibodies , Immunoglobulin G , Interleukin-17 , Pharmacology , Interleukin-6 , Genetics , Leukocytes, Mononuclear , Metabolism , Lupus Nephritis , Allergy and Immunology , RNA, MessengerABSTRACT
Objective To study the pathological characteristics and outcomes of IgA nephropathy(IgAN)presented with nephrotic syndrome (NS) and its relationship with prognosis. Methods From 1987 to 2002,clinical and pathological characteristics of IgAN presented with NS and its response to glucocorticoids therapy were reviewed and compared to non-nephrotic group. Results 7
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AIM:To investigate the regulatory role of nuclear factor κB (NF-κB) in the expression of interleukin-6 in mesangial cells (MC) induced by interleukin-1β.METHODS:Activation of NF-κB was measured by electrophoresis mobility shift assay (EMSA). RT/PCR and ELISA were used to detect IL-6 mRNA expression and IL-6 production, respectively.RESULTS:rhIL-1β could rapidly stimulate the activation of NF-κB in MC, and increase the expression of IL-6 mRNA and protein. PDTC, one of the inhibitor of NF-κB， could inhibit the expression of IL-6 in mRNA and protein in MC stimulated by rhIL-1β.CONCLUSION:IL-6 expression induced by IL-1β may be regulated by NF-κB in MC, NF-κB may modulate the immune-inflammatory reaction in glomerular disease.
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AIM: To investigate the role of reactive oxygen species (ROS) in transforming growth factor-?1 (TGF-?1)-induced regulation of plasminogen activator inhibitor-1 (PAI-1) expression and plasmin activity. METHODS: Growth arrested and synchronized rat mesangial cells were stimulated by TGF-?1. In some experiments,cells were pretreated with BSO or with antioxidant NAC. Intracellular ROS production was visualized using a fluorescent dye. PAI-1 protein secretion by mesangial cells was measured by Western blot and PAI-1 mRNA by both RT-PCR and Northern blot. Plasmin activity was determined using a synthetic fluorometric plasmin substrate. RESULTS: Exogenous TGF-?1 significantly increased intracellular ROS concentration and upregulated PAI-1 mRNA and protein expression in mesangial cells and reduced the plasmin activity. TGF-?1-induced upregulation of PAI-1 mRNA expression was exaggerated by BSO[DL-buthionine-(S,R)-sulfoximine]. NAC (N-acetylcysteine) effectively reversed TGF-?1-induced PAI-1 mRNA overexpression and plasmin activity decreasing. CONCLUSION: TGF-?1 increases intracellular ROS generation. ROS acts as a signaling molecular to mediate TGF-?1-induced PAI-1 overexpression and decrease in plasmin activity.
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AIM: To investigate the association of gene polymorphism at position 196 of tumor necrosis factor receptor Ⅱ (TNFRⅡ) with systemic lupus erythematosus (SLE) in Chinese, and establish recombinant retroviral vector to analyze the function of the TNFRⅡ 196M/R. METHODS: The genotype at position 196 of TNFRⅡ was determined by PCR-RFLP in 106 SLE patients and 119 healthy controls in china. Human TNFRⅡ196M cDNA were amplified by PCR and cloned into PMD18-T vector. Then, PMD18-TNFRⅡ196R was induced by site-directed mutagenesis. The recombinant T vector, PMD18-TNFRⅡ196M and PMD18-TNFRⅡ196R, were subcloned into retroviral vector PLXSN. Both normal and variant were transfected into rat mesangial cell. The effects of TNF? on production of sTNFRⅡ and IL-6 were study by ELISA. RESULTS: (1) The frequency of TNFRⅡ196R allele was significantly higher than those in controls (35.2% vs 14.3%, P
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Objective To investigate the antimicrobial resistance of pathogens causing complicated urinary tract infection. Methods Distribution and resistance of pathogens in 260 culture-positive hospitalized complicated urinary tract patients from 1995 to 2001 were analyzed. Results Gram-negative bacilli accounted for 77. 3% , with 44. 2% of E. Coli. Gram-positive cocci accounted for 16. 9% , with 11. 6% of Enterococci; and fungi accounted for 5. 8%. E. Coli had the highest resistance rate of 84. 1% for ampicillin. Resistance rate of E. Coli to amoxicillin/clavulate(21. 3% ) was significantly lower than that to ampicillin alone ( P
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Objective To explore the role of ROS in TGF ?1 induced changes of plasmin system in rat mesangial cells. Methods Growth arrested and synchronized rat mesangial cells were stimulated by 2 ng/ml TGF ?1 for 12 h. In some experiments cells were pretreated with BSO for 24 h or with antioxidant NAC for 1h. Intracellular ROS production was visualized using a fluorescent dye.The mRNA expression of tPA, uPA and PAI 1 was measured by RT PCR and PAI 1 protein secreted into media by ELISA assay.The activities of plasmin, uPA, tPA were determined using a synthetic fluorometric substrate. Results TGF ?1 significantly increased intracellular ROS concentration. 2 ng/ml TGF ?1 significantly upregulated PAI 1 mRNA and protein expression by 1 9 fold(P
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Objective To study the regulation of MMPs and TIMPs expression by VEGF in mouse mesangial cells (MMCs) . Methods Cultured MMCs were incubated with or without recombinant human VEGF for 12 hours. Protein levels of MMP2,MMP9,TIMP1 and TIMP2 in media were measured by Western blot analysis. MMP2 and MMP9 activities were measured by gelatin zymography. TIMP1 and TIMP2 mRNA expression in MMCs was analyzed by RT-PCR. Results VEGF(10 ng/ml) upregulated MMP2 and MMP9 protein secretion by MMCs (increased by 43% and 34% respectively, P
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AIM: To investigate the regulatory role of nuclear factor ?B (NF-?B) in the expression of interleukin-6 in mesangial cells (MC) induced by interleukin-1?.METHODS: Activation of NF-?B was measured by electrophoresis mobility shift assay (EMSA). RT/PCR and ELISA were used to detect IL-6 mRNA expression and IL-6 production, respectively.RESULTS: rhIL-1? could rapidly stimulate the activation of NF-?B in MC, and increase the expression of IL-6 mRNA and protein. PDTC, one of the inhibitor of NF-?B, could inhibit the expression of IL-6 in mRNA and protein in MC stimulated by rhIL-1?.CONCLUSION: IL-6 expression induced by IL-1? may be regulated by NF-?B in MC, NF-?B may modulate the immune-inflammatory reaction in glomerular disease.
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AIM: To investigate the effect of retinoic acid on proliferation of renal interstitial myofibroblasts in a rat model of the left unilateral ureteal obstruction (UUO). METHODS: UUO model was established by unilateral ligation of ureter in 36 SD rats. Rats were divided into 2 groups: Retinoic acid-treated group and control group, each with 18 rats. UUO rats were treated with either daily subcutaneous injection of 10 mg/kg body weight of all trans-retinoic acid or vehicle alone two days before the operation until being sacrificed. Groups of 6 rats were killed on day 3, 7 and 12 after ligation of the left ureter. The percentage of renal tubular lesion, interstitial fibrosis score, the number of interstitial myofibroblasts, the number of proliferating myofibroblasts and the expression of TGF?-1 mRNA were determined. RESULTS: There were significant accumulation and local proliferation of myofibroblasts in the interstitium of the UUO rats. On day 7 of the UUO model, the percentage of tubular lesions and interstitial fibrosis score were significantly lower in the retinoic acid-treated group than those in control group [(15.9?2.0)% vs (27.3?2.2)% and (0.47?0.12) vs (1.65?0.18), P
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AIM: To detect the association between the polymorphism of Fc receptor ? chain gene at position-29 in promoter and systemic lupus erythematosus(SLE). METHODS: The genotypes at position -29 in promoter of Fc receptor ? chain gene were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 180 patients with SLE and 140 ethnically matched controls in southern China. RESULTS: The frequencies of TT genotype(33.3%) and T allele (54 4%) at position -29 in patients with SLE were significantly higher than those in controls (17 9%, respectively), whereas, the frequencies of GG genotype (24 4%) and G allele (45 6%) in patients with SLE were remarkably lower than those in controls (31 4% and 57 1%, respectively) ( P 0 05) . CONCLUSION: Our results indicate that the T allele at position -29 in promoter of Fc receptor gene probably contributes to the susceptibility to SLE, but does not play a role in the occurrence of lupus nephritis.