Publications (13)34.82 Total impact
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Article: ATP-P2X4 Signaling Mediates NLRP3 Inflammasome Activation: A Novel Pathway of Diabetic Nephropathy.
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ABSTRACT: Tubulointerstitial inflammation plays a key role in the development of diabetic nephropathy (DN). Cytokines in the IL-1 family are the key pro-inflammatory cytokines of tubulointerstitial inflammation. Extracellular ATP can cause P2X receptors to activate the NOD-like receptor 3 (NLRP3) inflammasome and cause IL-1β and IL-18 maturation and release. We investigated the role of ATP-P2X4 signaling in NLRP3 inflammasome activation and renal interstitial inflammation characteristic of DN. Ex vivo studies, P2X4 showed increased expression in renal tubule epithelial cells in patients with nephropathy due to type 2 diabetes compared to those in the control group. Linear correlation analysis shows that P2X4 expression was positively related with urine IL-1β and IL-18 levels. Moreover, P2X4 expression was co-localized with NLRP3, IL-1β, and IL-18 expression. In vitro culture experiments showed NLRP3 protein expression, cleavage of caspase-1 and IL-1β, and release of IL-1β, IL-18 and ATP in HK-2 cells significantly increased after high glucose stimulation. However, apyrase, which consumes extracellular ATP, completely blocked the changes caused by high glucose. The P2 receptor antagonist suramin, P2X receptor antagonist TNP-ATP, P2X4 selective antagonist 5-BDBD, and P2X4 gene silencing attenuated NLRP3 expression, cleavage of caspase-1 and IL-1β, and release of IL-1β and IL-18 induced by high glucose. Taken together, these results suggest that ATP-P2X4 signaling mediates high glucose-induced activation of the NLRP3 inflammasome, regulates IL-1 family cytokine secretion, and causes the development of tubulointerstitial inflammation in DN.The international journal of biochemistry & cell biology 02/2013; · 4.89 Impact Factor -
Article: Anticubilin antisense RNA ameliorates adriamycin-induced tubulointerstitial injury in experimental rats.
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ABSTRACT: This study was designed to determine the effects of in vivo anticubilin antisense RNA on the uptake of albumin in tubules and on the tubulointerstitial injury in adriamycin-induced proteinuric rats. Adriamycin-treated rats were subjected to intrarenal delivery of adenoviral vectors encoding empty plasmid, cubilin sense RNA expression vector pAd-CUB or anticubilin antisense RNA expression vector pAd-ACUB on day 3. On days 14 and 28, half of the rats in each group were randomly selected to be killed, and blood samples, kidney tissues and 24-hour urine were collected. The diseased rats treated with pAdEasy-ACUB showed a 60% decrease in serum creatinine and glomerular filtration rate. Interestingly, the anticubilin antisense treatment led to a marked increase in albuminuria. Antisense treatment attenuated the histologic changes on both day 14 and day 28. The antisense treatment induced more than 60% recovery of adriamycin-induced injury, accompanied with 85% knockdown in the expression of cubilin protein and markedly decreased albumin deposition. Adriamycin induced an increase in the expression of monocyte chemoattractant protein-1, transforming growth factor-β and regulated on activation in normal T-cell expressed and secreted and the number of infiltrating cells, which was reversed by the antisense treatment. Anticubilin antisense RNA delivered by an adenoviral vector ameliorates albuminuria-induced glomerulosclerosis and tubulointerstitial damage in adriamycin nephrotic rats, indicating that cubilin could be a potential therapeutic target in proteinuric nephropathy.The American Journal of the Medical Sciences 12/2011; 342(6):494-502. · 1.39 Impact Factor -
Article: MiR-34 modulates Caenorhabditis elegans lifespan via repressing the autophagy gene atg9.
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ABSTRACT: Evidence for a regulatory role of the miR-34 family in senescence is growing. However, the exact role of miR-34 in aging in vivo remains unclear. Here, we report that a mir-34 loss-of-function mutation in Caenorhabditis elegans markedly delays the age-related physiological decline, extends lifespan, and increases resistance to heat and oxidative stress. We also found that RNAi against autophagy-related genes, atg4, bec-1, or atg9, significantly reversed the lifespan-extending effect of the mir-34 mutants. Furthermore, miR-34a inhibits Atg9A expression at the post-transcriptional level in vitro, and the miR-34a binding sequences in the 3'-UTR of Atg9A contributes to the modulation of Atg9A expression by miR-34a. Our results demonstrate that the C. elegans mir-34 mutation extends lifespan by enhancing autophagic flux in C. elegans, and that miR-34 represses autophagy by directly inhibiting the expression of the autophagy-related proteins Atg9 in mammalian cells.Age 11/2011; · 6.28 Impact Factor -
Article: Albumin overload induces apoptosis in renal tubular epithelial cells through a CHOP-dependent pathway.
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ABSTRACT: The proteinuria-induced apoptosis of proximal tubular cells (PTCs) plays a crucial role in renal tubulointerstitial injury in chronic kidney disease. Recent studies have shown that endoplasmic reticulum (ER) stress is involved in proteinuria-induced apoptosis of PTCs. Our study showed that albumin overload led to ER stress, CCAAT/enhancer-binding protein-homologous protein (CHOP), and PKR-like kinase (PERK) activation and to apoptosis of PTCs in proteinuria patients. The apoptotic index of proximal renal tubular cells in the nephrotic kidneys was about 13-fold higher than that in control kidneys. The increased tubular expression of GRP78, ORP150, and CHOP and nuclear localization of CHOP in nephrotic kidneys were also detected. The expression of GRP78, CHOP, PERK, and phosphorylated PERK increased proportionately with HSA overload in a dose- and time-dependent manner. Knockdown of CHOP by siRNA significantly reduced the HSA-induced apoptosis of HKC. The expression of PERK did not significantly change, but the phosphorylation of PERK increased. Furthermore, knockdown of PERK significantly inhibited HSA-induced CHOP expression, suppressing apoptosis in HKCs by 2.48-fold compared to controls. Overexpression of CHOP enhanced the apoptosis of HKC induced by albumin, no significant difference was observed in the expression of PERK, whereas the phosphorylation of PERK decreased. Our data indicated that proteinuria induces ER stress in renal tubular cells, which may subsequently lead to tubular damage through a PERK-CHOP-dependent pathway. This ER stress-induced apoptosis pathway may contribute to renal tubulointerstitial injury by proteinuria in chronic kidney disease.Omics: a journal of integrative biology 02/2010; 14(1):61-73. · 2.29 Impact Factor -
Article: Blockade of B-cell-activating factor suppresses lupus-like syndrome in autoimmune BXSB mice.
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ABSTRACT: B-cell-activating factor (BAFF), a member of the tumour necrosis factor superfamily, plays a critical role in the maturation, homeostasis and function of B cells. In this study, we demonstrated the biological outcome of BAFF blockade in BXSB murine lupus model, using a soluble fusion protein consisting of human BAFF-R and human mutant IgG4 Fc. Mutation of Leu(235) to Glu in IgG4 Fc eliminated antibody-dependent cell cytotoxicity (ADCC) and complement lysis activity, and generated a protein devoid of immune effector functions. Treatment of BXSB mice with BAFF-R-IgG4mut fusion protein for 5 weeks resulted in significant B-cell reduction in both the peripheral blood and spleen. Treated mice developed lower proteinuria, reduced glomerulonephritis and much delayed host death than untreated animals. Thus, BAFF blockade with BAFF-R-IgG4mut protein is an effective strategy to treat B-cell-mediated lupus-like pathology. Moreover, compared with other IgG isotypes with undesired effector functions, mutant IgG4 Fc should prove useful in constructing novel therapeutic reagents to block immune molecule signalling in various diseases.Journal of Cellular and Molecular Medicine 08/2009; 14(6B):1717-25. · 4.13 Impact Factor -
Article: Mutual activation of CD4+ T cells and monocytes mediated by NKG2D-MIC interaction requires IFN-gamma production in systemic lupus erythematosus.
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ABSTRACT: The activating receptor NKG2D is mainly expressed by human CD8(+) T cells and NK cells but normally absent on CD4(+) T cells. However, a subset of autoreactive NKG2D(+)CD4(+) T cells has been found to exist in some autoimmune disease such as rheumatoid arthritis (RA) and to participate in the imbalance of immune response and inflammation. Up to date this observation has been extended to some autoimmune diseases such as RA and Crohn's disease and the mechanism underlying the presence of this type of NKG2D(+)CD4(+) T cells has not been delineated yet. In this study, we found that a substantial proportion of CD4(+) T cells expressed NKG2D in the PBMC of SLE patients. We also found that monocytes in SLE aberrantly expressed the NKG2D ligand of MHC class I chain-related (MIC) molecules and membrane-bound IL-15 (mIL-15) at the cell surface. When cultured with the sera from SLE patients, the monocytes from healthy volunteers could be induced to express MIC and mIL-15. However, this induced expression of MIC and mIL-15 could be blocked with anti-IFN-gamma receptor (anti-IFN-gammaR) antibody. We further demonstrated that NKG2D could be induced on normal CD4(+) T cells either cocultured with monocytes from patients with SLE, or monocytes from healthy volunteers but pretreated with IFN-gamma. Moreover, Th1 cytokines were found to be produced by NKG2D(+)CD4(+) T cells in the coculture system. By transwell assay, we found that both NKG2D expression and Th1 cytokines production depended on the cell-cell contact. These results indicate that the elevated sera IFN-gamma may be responsible for MIC and mIL-15 induction on monocytes in SLE; mIL-15 on monocytes contribute to NKG2D receptor induction on a subset of CD4(+) T cells. Moreover, CD14(+) monocytes promote NKG2D(+)CD4(+) T cells activation through the NKG2D-MIC engagement in the pathogenesis of SLE.Molecular Immunology 03/2009; 46(7):1432-42. · 2.90 Impact Factor -
Article: Insertion of a targeting peptide on capsid surface loops of human papillomavirus type-16 virus-like particles mediate elimination of anti-dsDNA Abs-producing B cells with high efficiency.
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ABSTRACT: The purpose of this study was to design chimeric human papillomavirus type-16 L1 virus-like particles (VLPs) and to explore the potential capacity of elimination to anti-dsDNA antibody-producing B cells. To test it, VLPs were achieved by combination of human papillomavirus type-16 L1 proteins inserted into a targeting peptide (DWEYSVWLSN) and plasmids encoding diphtheria toxin A ligand. Additionally, VLPs were cocultured with target cells to assess the killing efficiency by lactate dehydrogenase assay in vitro. Lastly, lupus-prone (BWF1) mice vaccinated with VLPs were used as a model to assess the killing efficiency in vivo. The results showed that the VLPs were constructed successfully, and possessed the potential of killing anti-dsDNA antibody-producing B cells with high efficiency. The findings indicate the possibility that the VLPs ablate autoreactive B cells represents a novel strategy in the immunotherapy of autoantibody-mediated diseases.Journal of immunotherapy (Hagerstown, Md.: 1997) 02/2009; 32(1):36-41. · 3.20 Impact Factor -
Article: Expression of renal cubilin and its potential role in tubulointerstitial inflammation induced by albumin overload
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ABSTRACT: Sustained proteinuria is an independent risk factor leading to kidney fibrosis and end-stage renal failure. Over-reabsorption of filtered proteins, notably albumin, has been proved to trigger interstitial inflammation and fibrosis in proteinuric renal disease. Cubilin, an endocytic receptor expressed on the renal tubular brush border, is responsible for albumin reabsorption in physiologic condition. However, little is known about whether it is required for activation of tubular cells induced by albumin overload. In this work, we investigated the change of cubilin expression and its potential role in albumin-induced up-regulation of chemokines synthesis in vivo and in vitro. Twenty-six patients with nephrotic syndrome were enrolled in this study. Proximal tubule uptake of albumin, expression of apical membrane cubilin and infiltrating cells in kidney interstitium were determined by immunocytochemistry. In vitro, the transcription of cubilin in HK2 cells after exposure to albumin was analyzed by real-time PCR. Endocytosis of albumin in HK2 cells was examined by fluorescent microscope. The influence of inhibition of cubilin on albumin-induced expressions of monocyte chemoattractant protein 1 (MCP-1) and regulated upon activation normal T-cell expressed and secreted (RANTES) was investigated by Western blot. The intensity of luminal cubilin and tubular accumulation of albumin were significantly increased in nephrotic kidneys. The expression of MCP-1 and RANTES was up-regulated, and there were spatial relationships in localization between these chemokines and cubilin as well as intracellular albumin in kidney tissues. Infiltration of CD-3 and ED-1-positive cells was predominant in tubulointerstitial areas displaying signs of increases of cubilin expression and albumin accumulation. In vitro, the transcription of cubilin mRNA in HK2 cells was enhanced after 24 h exposure to albumin in a dose-dependent manner. Inhibition of endocytosis of albumin by antisense cubilin nucleotide markedly reduced expression of MCP-1 and RANTES. Cubilin was required for handling a greater amount of protein in nephrotic status and albumin-induced production of MCP-1 and RANTES by renal tubular cells, which further initiated tubulointerstitial inflammation in proteinuric disease.Frontiers of Medicine in China 01/2008; 2(1):25-34. -
Article: Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy.
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ABSTRACT: Renal tubulointerstitial injury plays an important role in the development of IgA nephropathy (IgAN), the most common form of glomerulonephritis. Few currently in use biomarkers can sensitively detect the earliest signs of renal tubular injury, hindering our efforts to launch preventive and therapeutic measures for this disorder in a timely manner. Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that is rapidly released from not only neutrophils but also a variety of cell types upon inflammation and tissue injury. Its small molecular size and protease resistance could render it an excellent biomarker of renal injury in IgAN. In this study, we tested this hypothesis by measuring urinary levels of NGAL, creatinine and N-acetyl-beta-D-glucosaminidase (NAG) in 40 healthy individuals and 70 IgAN patients with various disease severities. The urinary NGAL levels and NGAL/creatinine values were significantly upregulated in Lee grade III IgAN patients, in correlation with progressive glomerular mesangial proliferation and tubulointerstitial injury. Compared with urinary NAG levels, the urinary NGAL levels elevated much more drastically and can be readily detected even in Lee grade II IgAN patients when their NAG levels showed almost no change. Our findings suggest the promising use of urinary NGAL as an early biomarker for tubulointerstitial injury of IgA nephropathy and perhaps other types of renal disease in general.Clinical Immunology 06/2007; 123(2):227-34. · 4.05 Impact Factor -
Article: Effect of bactericidal/permeability-increasing protein on sepsis induced by intra-abdominal infection in rats.
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ABSTRACT: OBJECTIVE: To investigate the effect and mechanism of bactericidal/permeability-increasing protein (BPI) on sepsis induced by intra-abdominal infection in rats. METHODS: Cecal ligation and puncture (CLP) was made on 20 rats with sepsis induced by intra-abdominal infection. BPI or equal volume of physiological saline (PS) was intra-abdominally given immediately and 12 h after CLP, respectively (2.5 mg/kg of BPI each time). Plasma endotoxin levels were determined with limulus amebocyte chromogenic assay. RESULTS: (1) The survival time in BPI group was significantly higher than that in PS group. (2) The values of the mean arterial pressure (MAP), the left ventricular systolic pressure (LVSP), the isovolumic ventricular pressure (IP), and the maximal change of left intraventricular pressure (+/-dp/dtmax) in BPI group, although decreasing, were markedly higher than those in PS group. (3) Plasma glutamic-pyruvic transaminase (GPT) and urea nitrogen levels in BPI group, though increasing, were obviously lower than those in PS group. (4) There was no significant change of plasma endotoxin levels in BPI group, while plasma endotoxin levels markedly increased in PS group. CONCLUSIONS: BPI has obvious protective effect on sepsis induced by intra-abdominal infection, which might be related to its neutralization of endotoxin.Chinese Journal of Traumatology (English Edition) 12/1999; 2(2):84-86. -
Article: Protective effect of bactericidal/permeability-increasing protein in mice with E. coli sepsis.
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ABSTRACT: OBJECTIVE: To investigate the effect of bactericidal/permeability-increasing protein(BPI) on the outcome of sepsis in mice and its possible mechanism. METHODS: Sepsis was induced by injection of 2x10(6) colony-formed unit E. coli J5 via the tail vein. BPI of 5 mg/kg or equal volume of normal saline(NS) were injected intravenously at the same time. Endotoxin and TNFalpha levels in serum were assayed using a chromogenic limulus amebocyte lysate test and ELISA respectively. RESULTS: Seventy-two hour survival rate of septic mice was significantly higher in the BPI group (15/18) than in the NS group(8/18, P<0.01). Serum endotoxin levels in the BPI group (1.3+/-0.3 and 0.7+/-0.4 &mgr;g/L) were significantly lower than those in the NS group (3.9+/-0.8 and 2.5+/-0.9 &mgr; g/L, P<0.01) 0.5 and 1 hour following injection of bacteria respectively. The peak levels of serum tumor necrosis factor-alpha(TNFalpha)in the BPI group (1.9+/-0.6 &mgr;g/L) were also markedly lower than those in the NS group (3.8+/-0.8 &mgr;g/L, P<0.01) 1.5 hours following bacterial injection. But there was no significant difference in blood bacterial count between the BPI and NS groups 0.5, 1.5 and 3.0 hours after injection of bacteria. CONCLUSIONS: BPI has a marked protective effect on E. coli sepsis, which might be related to its action against bacterial endotoxin and its inhibition of TNFalpha production in sepsis.Chinese Journal of Traumatology (English Edition) 12/1998; 1(1):21-24. -
Article: Delivering PD-1 inhibitory signal concomitant with blocking ICOS co-stimulation suppresses lupus-like syndrome in autoimmune BXSB mice.
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ABSTRACT: BXSB mice spontaneously develop an autoimmune syndrome characterized by hypergammaglobulinemia, autoantibody production, and the development of fatal glomerulonephritis that closely resembles systemic lupus erythematosus (SLE) in humans. While blocking positive T cell co-stimulation has shown effectiveness in preventing the onset of murine lupus, deliberate delivering negative co-stimulation to halt unwanted T and B cell activation has not been tested. We developed a recombinant adenovirus containing the full-length mouse PD-L1 gene (Ad.PD-L1) to engage the immunoinhibitory receptor PD-1 on activated lymphocytes to prevent lupus nephritis in BXSB mice. This strategy was further reinforced by concomitant injection of anti-ICOSL(B7h) mAb to block ICOS-mediated co-stimulation. The combined therapy dramatically delayed the onset of proteinuria, effectively inhibited IgG autoantibody production, and significantly reduced hypercellularity and deposition of IgG in glomeruli, resulting in almost complete amelioration of lupus nephritis in these animals. Our results indicate the therapeutic potential of simultaneous stimulation of PD-1-mediated pathway and blockade of ICOS-B7h co-stimulation in the prevention of human lupus nephritis.Clinical Immunology 118(2-3):258-67. · 4.05 Impact Factor -
Article: Sodium dicarboxylate cotransporter-1 expression in renal tissues and its role in rat experimental nephrolithiasis.
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ABSTRACT: Nephrolithiasis is a common disease with a high recurrence rate; however, calcium stone pathogenesis remains unknown because of complex multiple factors. Hypocitraturia induced by citrate transport disturbance is known to be involved in nephrolithiasis development. Sodium dicarboxylate cotransporter (NaDC) mediates citrate uptake from the renal proximal tubule. However, the role of NaDC in nephrolithiasis is unclear. This study aimed to investigate NaDC-1 expression in rat renal proximal tubule epithelial cells and its relationship with experimental nephrolithiasis. Male Wastar rats were divided into control, ethylene glycol (EG)-treated and potassium citrate-treated groups. Calcium oxalate (CaOx) crystal deposition and histological changes in the kidneys were examined with anatomical and light microscopes. The plasma and urinary biochemical parameters, such as citrate, oxalate etc, were analyzed by routine biochemical methods. NaDC-1 mRNA expression in kidneys was determined by northern blot analysis, the change in NaDC-1 protein abundance was detected by immunohistochemistry. It was found that NaDC-1 expression and its mRNA significantly increased in the EG group when compared with controls. Increased NaDC-1 expression was associated with a decline in urinary citrate excretion. Potassium citrate administration could significantly down-regulate NaDC-1 expression and its mRNA, and elevate urinary citrate content alleviate renal pathological changes and reduce nephrolithiasis occurrence. Increased NaDC-1 expression on the renal proximal tubule epithelial cells could play an important role in nephrolithiasis development, suggesting it could be a therapeutic target for the treatment of nephrolithiasis.Journal of nephrology 17(1):34-42. · 1.65 Impact Factor
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2013
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The Third Military Medical University
Chongqing, Chongqing Shi, China
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