scholarly journals Evidence for increased synthesis of complement C4 in the renal epithelium of rats with passive Heymann nephritis.

1997 ◽  
Vol 8 (2) ◽  
pp. 214-222 ◽  
Author(s):  
W Zhou ◽  
P A Andrews ◽  
Y Wang ◽  
J Wolff ◽  
J Pratt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Tissue Injury ◽  
Membrane Attack Complex ◽  
Classical Pathway ◽  
Dependent Manner ◽  
Barrier Dysfunction ◽  
Renal Epithelium ◽  
Renal Tubular Epithelium ◽  
Heymann Nephritis

Passive Heymann nephritis (PHN) is a complement-dependent model of immune complex glomerulonephritis. This study investigated the contribution of local complement synthesis by studying gene expression of the classical pathway component C4 in relation to the site of the tissue injury and the development of proteinuria induced by the pathogenic antibody (sheep anti-GP330). This study, using in situ hybridization, found that C4 mRNA expression was increased in the glomerular epithelium and the proximal renal tubular epithelium in a distribution similar to that of the targeted GP330 antigen. The total cortical C4 mRNA expression assessed by semiquantitative polymerase chain reaction (PCR) increased in a time-dependent manner (P < 0.05), coincident with the onset and progression of proteinuria, and peaking 11 to 14 days after the induction of the disease. These data suggest a link, in place and time, between local complement gene expression and glomerular barrier dysfunction induced by anti-GP330. It is postulated that increased epithelial synthesis of C4 stimulated by the engagement of GP330 enhances the formation of the membrane attack complex of complement through its classical pathway, and, hence, the formation of complement-mediated injury.

scholarly journals Paternal High Fat Diet and Exercise Regulate Sperm miRNA to Alter Placental Inflammation and Nutrient Transporter Expression in a Sex-Dependent Manner

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1024-1024
Author(s):  
Kate Larson ◽  
Amy Bundy ◽  
James Roemmich
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Mirna Expression ◽  
Placental Tissue ◽  
Tissue Growth ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
High Fat ◽  
Diet And Exercise ◽  
Nutrient Transporter

Abstract Objectives We have shown that male offspring (F1) of fathers (F0) fed a high fat (HF) diet and exercised had greater skeletal muscle insulin signaling and reduced T2DM risk compared to fathers fed HF diet and remain sedentary. The current study extends this work by hypothesizing that F0 HF diet and exercise regulate F1 T2DM risk by early alterations in epigenetics of placental tissue growth via changes in sperm miRNA expression. Methods To test these hypotheses, three-week old male C57BL/6 mice were fed a normal-fat (NF) diet (16% fat) or a HF diet (45% fat) and assigned to either voluntary wheel running exercise or cage activity for 3 months prior to mating with NF diet fed dams. F0 sperm and placental tissue samples were collected to determine changes in placental and fetal weights, placental gene expression, and F0 sperm miRNA expression. Results F0 sperm miRNA 193b expression was decreased while miRNA 204 was increased by paternal exercise. Protein expression of di-methylated histone 3 lysine 9 was decreased with F0 HF diet. Placental and fetal tissue weights were decreased by F0 HF diet in F1 males while no changes in the F1 females. Placental proinflammatory cytokine mRNA expression, including IL-1 beta and TNF-alpha, was reduced by paternal exercise while nutrient transporter mRNA expression was decreased by paternal HF diet only in the placentae of F1 females. Treatment of primary placental cell with miRNA 193 inhibited TNF-alpha mRNA expression. In addition, treatment of the same cells with TNF-alpha increased SLC6a19. Moreover, paternal exercise increased body weight at weaning in a female offspring. Conclusions These results demonstrate that placental tissue weight, placental nutrient transporter gene expression and fetal weights are altered by paternal exercise while placental inflammatory gene expression are influenced by paternal exercise in offspring in a sex-specific manner. Funding Sources This work was supported by USDA ARS Project #3062–51,000-054–00D.

Heme Oxygenase-1(HO-1): A Promising Novel Target Molecule for Overcoming Imatinib Resistance in Chronic Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4242-4242
Author(s):  
Jishi Wang
Keyword(s):  
Gene Expression ◽  
Chronic Myeloid Leukemia ◽  
Mrna Expression ◽  
Myeloid Leukemia ◽  
K562 Cells ◽  
Leukemia Cell Line ◽  
Dependent Manner ◽  
Rt Pcr ◽  
Imatinib Resistant ◽  
Resistant Cells

Abstract Objective : HO-1 is a microsomal enzyme catalyzing the first, rate-limiting step in degradation of heme, HO-1 is a inducible isoform of HO, it can be strongly induced in response to cellular stress and diverse oxidative stimuli, including its substrate heme, Many studies have convincingly shown that HO-1 is a cytoprotective and antiapoptotic enzyme. the objective of this study was to investigate the influence on the K562 cell growth and apoptosis after hemin-induced HO-1 expression, and to investigate the influence on K562 cells and imatinib-resistant CML cells after ZnPPIX-induced HO-1 inhibition. Methods: different concentrations hemin (0umol/l A20umol/l 30umol/l)was used respectively to induce HO-1 expression of cultured chronic myeloid leukemia cell line K562, then detected HO-1 mRNA expression under different time by RT-PCR, and MTT was used to detected the viability of K562 cells. In addition, we used STI571(2 μmol/L) deal with the hemin-induced cells, then confirm HO-1 protective effect against STI571 use MTT. Then ZnPPIX was used to inhibition HO-1 expression of K562 and imatinib-resistant cells, similarly, RT-PCR and MTT was used for analyzed. Results: The HO-1 mRNA was not tested when absence of hemin, 8h after treated with hemin of 20 μmol/L, we can test the HO-1 mRNA expression, and at 16h the expression is reach to the peak, 16h after treated hemin under different concentrations (10umol/l, 20umol/l, 30umol/l), we found the expression is in a dose-dependent manner. In the group of 10 umol/l and 20 umol/l, the survival of cells is significantly increased in comparison to the control and also have significantly difference in the two groups(p&lt;0.05), in the group of 20 μmol/L, 16h to 48h after hemin-induced, the survival of cells presents a time-dependent manner. In the group of 10μmol/L and 20 μmol/L, exposure of K562 cells to STI571 resulted in a substantial decrease of cell viability in comparison to the STI571 single treatment group(p&lt;0.05). ZnPPIX-induced HO-1 inhibition leads to induction of apoptosis in K562 cells, having significant difference with the control group(p&lt;0.05). ZnPPIX-induced HO-1 inhibition can suppress the survival of imatinib-resistant cells(p&lt;0.05). Conclusion: our studies have shown that hemin-induced HO-1 gene expression may promote the proliferation of K562 cells, and can against the cell apoptosis. And we found hemin-induced HO-1 gene expression can protect K562 cells against STI571-induced apoptosis, ZnPPIX-induced HO-1 inhibition leads to decreased viability of imatinb-resistant CML cells. these all indicates HO-1 may represent a novel targeting in CML.

scholarly journals Isoproterenol is a positive regulator of the suppressor of cytokine signaling-3 gene expression in 3T3-L1 adipocytes

2002 ◽  
Vol 175 (3) ◽  
pp. 727-733 ◽  
Author(s):  
M Fasshauer ◽  
J Klein ◽  
U Lossner ◽  
R Paschke
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Mrna Expression ◽  
Adenylyl Cyclase ◽  
Insulin Signaling ◽  
Tnf Alpha ◽  
Cytokine Signaling ◽  
Dependent Manner ◽  
Suppressor Of Cytokine Signaling ◽  
Beta Adrenergic

SOCS (suppressor of cytokine signaling)-3 has recently been shown to be an insulin- and tumor necrosis factor (TNF)-alpha-induced negative regulator of insulin signaling. To further clarify a potential involvement of SOCS-3 in the development of insulin resistance, we measured differentiation-dependent SOCS-3 mRNA expression in 3T3-L1 adipocytes and studied its regulation by various hormones known to impair insulin signaling using quantitative real-time RT-PCR. There was a differentiation-dependent downregulation of SOCS-3 mRNA by 50% over the 9 day adipocyte differentiation course. Interestingly, besides insulin and TNF-alpha, chronic treatment of differentiated 3T3-L1 cells with 10 microM isoproterenol for 16 h stimulated SOCS-3 gene expression by about 3.5-fold. Furthermore, isoproterenol stimulated SOCS-3 mRNA expression in a dose-dependent manner with significant activation detectable at concentrations as low as 10 nM isoproterenol. Moreover, a strong 27- and 47-fold activation of SOCS-3 mRNA expression could be seen after 1 h of isoproterenol and GH treatment respectively. The stimulatory effect of isoproterenol could be almost completely reversed by pretreatment of 3T3-L1 cells with the beta-adrenergic antagonist propranolol. Finally, isoproterenol's action could be mimicked by stimulation of G(S)-proteins with cholera toxin and of adenylyl cyclase with forskolin and dibutyryl cAMP. Taken together, our results demonstrate a differentiation-dependent downregulation of SOCS-3 in adipocytes and suggest that SOCS-3 gene expression is stimulated by beta-adrenergic agents via activation of a G(S)-protein-adenylyl cyclase-dependent pathway. As SOCS-3 is a novel inhibitor of insulin signaling, the data support a possible role of this protein as a selectively regulated mediator of catecholamine-induced insulin resistance.

Mesenchymal Stem Cells Express the Surface Receptor Calreticulin (cC1qR) and Complement C1q Chemoattracts Them.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3855-3855
Author(s):  
Yuanyuan Qiu ◽  
Leah A. Marquez-Curtis ◽  
Anna Janowska-Wieczorek
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Signaling Pathways ◽  
Conflicts Of Interest ◽  
Tissue Injury ◽  
Akt Signaling ◽  
Classical Pathway ◽  
Dependent Manner ◽  
Hematopoietic Stem ◽  
Surface Receptor

Abstract Abstract 3855 Complement cleavage fragments play an important role in the trafficking of hematopoietic stem/progenitor cells as reported by us (Blood 2003;101:3784; Exp Hematol 2010;38:321; Transfusion Sept 2010), as well as of mesenchymal stem cells (MSC) as reported by others (J Immunol 2009;182:3827). Because MSC have a great potential for tissue regeneration and cellular therapies, in this study we investigated the mechanisms of migration of MSC to injured sites. As complement cascade is activated upon tissue injury we examined whether complement component 1 subcomponent q (C1q), the initiator of the classical pathway of complement activation, plays a role in the migration of MSC, and which C1q receptors (CR1, gC1qR, calreticulin (cC1qR), CD93) are expressed on MSC and could be involved in their migration. We previously reported that matrix metalloproteinases (MMPs), especially membrane type 1 (MT1)-MMP and MMP-2, regulate the migration of MSC (Stem Cells, 2006, 24:1254); therefore in this study we examined the effects of C1q on MMP expression and migration of MSC. Human MSC isolated from cord blood and bone marrow were maintained for 3–6 passages and characterized by adipocyte and osteoblast differentiation. We used chemoinvasion across the reconstituted basement membrane Matrigel to evaluate the migration of MSC, RT-PCR and flow cytometry to determine the expression of C1q receptors and, upon stimulation with C1q, zymography and Western blot to examine the expression of MMPs and ERK1/2 and PI3K/Akt signaling pathways. We found that MSC were chemoattracted by a C1q gradient in a dose-dependent manner, and MSC expressed transcripts for gC1qR, CD93 and cC1qR, but only calreticulin protein was detected on the surface of MSC. Specific antibody against calreticulin (anti-cC1qR antibody) inhibited the trans-Matrigel chemoinvasion of MSC towards C1q. Moreover, stimulation of MSC with C1q (10 μ g/mL) increased MT1-MMP expression, but no changes in MMP-2 secretion were observed. Trans-Matrigel migration of MSC towards C1q was also reduced by the MT1-MMP inhibitor EGCG. Further, the ERK1/2 inhibitor PD98059 and the PI3K inhibitor Ly294002 decreased the chemoinvasion of MSC towards C1q. In conclusion, this study indicates that: 1) C1q exerts chemoattractant activity towards MSC through its surface receptor calreticulin; 2) MT1-MMP regulates the C1q-induced trans-Matrigel migration of MSC; and 3) both the ERK1/2 and PI3K/Akt signaling pathways are involved in this process. These findings demonstrate a broader regulatory role for C1q, which functions as a chemotactic factor for MSC through its binding to surface calreticulin, and suggest a newly-found mechanism for the migration of MSC which may be important for its clinical use. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chemokine gene expression in bone marrow stromal cells: downregulation with sodium salicylate

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2541-2550 ◽  
Author(s):  
SC Gautam ◽  
KR Pindolia ◽  
CJ Noth ◽  
N Janakiraman ◽  
YX Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Mrna Expression ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Sodium Salicylate ◽  
Marrow Stromal Cells ◽  
Dependent Manner ◽  
Chemokine Gene ◽  
Chemokine Gene Expression

Abstract Chemotactic cytokines, chemokines, have been shown to influence the proliferation of hematopoietic progenitor cells. Thus, regulation of chemokine production by bone marrow accessory cells is a critical aspect of stromal cell regulation of hematopoiesis. We have previously reported that monocyte chemotactic protein-1 (MCP-1 or MCP-1/JE) and interferon inducible protein 10 kD (IP-10) are both induced in murine bone marrow stromal cells +/(+)-1.LDA11 after stimulation with the inflammatory agents interleukin-1 alpha (IL-1 alpha), interferon-gamma (IFN-gamma), or lipopolysaccharide (LPS). In the present study, we have investigated the effect of sodium salicylate, an antiinflammatory agent, on the IL-1 alpha-induced expression of MCP-1/JE and IP-10 genes in stromal cells. Sodium salicylate attenuates the levels of MCP-1/JE and IP-10 mRNA in a concentration- and time-dependent manner. The suppression of MCP-1/JE mRNA is reversible, whereas IP-10 mRNA expression is more or less irreversibly affected as its recovery from the effect of sodium salicylate is slow and partial. Sodium salicylate-mediated suppression of mRNA expression is attributable neither to de novo synthesis of intermediary protein(s) nor to the destabilization of mature mRNA transcripts. On the other hand, sodium salicylate downregulates the transcriptional activity of both genes. Furthermore, IL-1 alpha induces activation of transcription factor nuclear factor (NF)-kB, and sodium salicylate suppresses it in a dose-dependent manner. We conclude that while posttranscriptional events remain unaffected, inhibition of NF-kB activation by sodium salicylate may account for the suppression of chemokine gene expression at the transcriptional level.

scholarly journals Proinflammatory Effects of Diesel Exhaust Nanoparticles on Scleroderma Skin Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
A. Mastrofrancesco ◽  
M. Alfè ◽  
E. Rosato ◽  
V. Gargiulo ◽  
C. Beatrice ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Cytokine Gene Expression ◽  
Unknown Etiology ◽  
Dependent Manner ◽  
Collagen Types ◽  
Normal Cells ◽  
Complex Disorders ◽  
Mrna Gene

Autoimmune diseases are complex disorders of unknown etiology thought to result from interactions between genetic and environmental factors. We aimed to verify whether environmental pollution from diesel engine exhaust nanoparticulate (DEP) of actually operating vehicles could play a role in the development of a rare immune-mediated disease, systemic sclerosis (SSc), in which the pathogenetic role of environment has been highlighted. The effects of carbon-based nanoparticulate collected at the exhaust of newer (Euro 5) and older (Euro 4) diesel engines on SSc skin keratinocytes and fibroblasts were evaluatedin vitroby assessing the mRNA expression of inflammatory cytokines (IL-1α, IL-6, IL-8, and TNF-α) and fibroblast chemical mediators (metalloproteases 2, 3, 7, 9, and 12; collagen types I and III; VEGF). DEP was shown to stimulate cytokine gene expression at a higher extent in SSc keratinocytes versus normal cells. Moreover, the mRNA gene expression of all MMPs, collagen types, and VEGF genes was significantly higher in untreated SSc fibroblasts versus controls. Euro 5 particle exposure increased the mRNA expression of MMP-2, -7, and -9 in SSc fibroblasts in a dose dependent manner and only at the highest concentration in normal cells. We suggest that environmental DEP could trigger the development of SSc acting on genetically hyperreactive cell systems.

Interferon-γ suppresses activin A/NF-E2 induction of erythroid gene expression through the NF-κB/c-Jun pathway

2014 ◽  
Vol 306 (4) ◽  
pp. C407-C414 ◽  
Author(s):  
Wei-Hwa Lee ◽  
Ming-Hui Chung ◽  
Yu-Hui Tsai ◽  
Ju-Ling Chang ◽  
Huei-Mei Huang
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Luciferase Activity ◽  
Globin Gene ◽  
Activin A ◽  
Dependent Manner ◽  
Promoter Activation ◽  
Ifn Γ ◽  
Globin Promoter ◽  
Dose Dependent

Interferon (IFN)-γ is a proinflammatory cytokine that is linked to erythropoiesis inhibition and may contribute to anemia. However, the mechanism of IFN-γ-inhibited erythropoiesis is unknown. Activin A, a member of the transforming growth factor (TGF)-β superfamily, induces the erythropoiesis of hematopoietic progenitor cells. In this study, a luciferase reporter assay showed that IFN-γ suppressed activin A-induced ζ-globin promoter activation in K562 erythroblast cells in a dose-dependent manner. Activin A reversed the suppressive effect of IFN-γ on the luciferase activity of ζ-globin promoter in a dose-dependent manner. IFN-γ also suppressed the activation of activin A-induced α-globin promoter. IFN-γ reduced the mRNA expression of α-globin, ζ-globin, NF-E2p45, and GATA-1 induced by activin A. The results also showed that IFN-γ induced c-Jun expression when NF-κBp65 and c-Jun bound to two AP-1-binding sites on the c-Jun promoter. The luciferase activity of α-globin and ζ-globin promoters were enhanced by wild-type c-Jun and eliminated by dominant-negative (DN) c-Jun. The suppressive effects of IFN-γ on the mRNA expression of α-globin and ζ-globin were absent in cells expressing DN c-Jun. The ability of NF-E2 to enhance activin A-induced ζ-globin promoter activation decreased when c-Jun was present, and IFN-γ treatment further enhanced the decreasing effect of c-Jun. Chromatin immunoprecipitation revealed that NF-E2p45 bound to the upstream regulatory element (HS-40) of the α-globin gene cluster in response to activin A, whereas c-Jun eliminated this binding. These results suggest that IFN-γ modulates NF-κB/c-Jun to antagonize activin A-mediated NF-E2 transcriptional activity on globin gene expression.

scholarly journals Effects of moderate global maternal nutrient reduction on fetal baboon renal mitochondrial gene expression at 0.9 gestation

2015 ◽  
Vol 308 (11) ◽  
pp. F1217-F1228 ◽  
Author(s):  
Susana P. Pereira ◽  
Paulo J. Oliveira ◽  
Ludgero C. Tavares ◽  
António J. Moreno ◽  
Laura A. Cox ◽  
...  
Keyword(s):  
Gene Expression ◽  
Energy Metabolism ◽  
Mrna Expression ◽  
Renal Dysfunction ◽  
Later Life ◽  
Chow Diet ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Nutrient Reduction ◽  
Mitochondrial Energy Metabolism

Early life malnutrition results in structural alterations in the kidney, predisposing offspring to later life renal dysfunction. Kidneys of adults who were growth restricted at birth have substantial variations in nephron endowment. Animal models have indicated renal structural and functional consequences in offspring exposed to suboptimal intrauterine nutrition. Mitochondrial bioenergetics play a key role in renal energy metabolism, growth, and function. We hypothesized that moderate maternal nutrient reduction (MNR) would adversely impact fetal renal mitochondrial expression in a well-established nonhuman primate model that produces intrauterine growth reduction at term. Female baboons were fed normal chow diet or 70% of control diet (MNR). Fetal kidneys were harvested at cesarean section at 0.9 gestation (165 days gestation). Human Mitochondrial Energy Metabolism and Human Mitochondria Pathway PCR Arrays were used to analyze mitochondrially relevant mRNA expression. In situ protein content was detected by immunohistochemistry. Despite the smaller overall size, the fetal kidney weight-to-body weight ratio was not affected. We demonstrated fetal sex-specific differential mRNA expression encoding mitochondrial metabolite transport and dynamics proteins. MNR-related differential gene expression was more evident in female fetuses, with 16 transcripts significantly altered, including 14 downregulated and 2 upregulated transcripts. MNR impacted 10 transcripts in male fetuses, with 7 downregulated and 3 upregulated transcripts. The alteration in mRNA levels was accompanied by a decrease in mitochondrial protein cytochrome c oxidase subunit VIc. In conclusion, transcripts encoding fetal renal mitochondrial energy metabolism proteins are nutrition sensitive in a sex-dependent manner. We speculate that these differences lead to decreased mitochondrial fitness that contributes to renal dysfunction in later life.

scholarly journals Bromide impairs the circadian clock and glycolytic homeostasis via disruption of autophagy in rat H9C2 cardiomyocytes

2019 ◽  
Author(s):  
Yicheng Jiang ◽  
Yang Gu ◽  
Hai Xu ◽  
Xiaoyi Tian ◽  
Xuefeng Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Viability ◽  
Circadian Clock ◽  
Mrna Expression ◽  
Clock Genes ◽  
Expression Patterns ◽  
Sodium Bromide ◽  
Circadian Oscillation ◽  
Dependent Manner ◽  
H9c2 Cardiomyocytes

Abstract Background Trace elements function as essential cofactors that are involved in various biochemical processes in mammals. Autophagy is vital for nutrient supplement, which is an important Zeitegber for the circadian homeostasis in heart. Here, we considered the possibility that autophagy, as well as the cardiomyocyte clock and glycolysis are interlinked. Detrimental effects were observed when cardiac system is exposed to bromine containing drugs. This study investigated the effects and mechanisms of bromide on the circadian clock and glycolytic metabolism of H9C2 cardiomyocytes. Methods H9C2 cardiomyocytes were incubated with sodium bromide at indicated doses for 24 hours, cell viability, mRNA expression of clock genes, glycolytic genes and autophagic genes were examined using various cellular and molecular approaches. Also, circadian oscillation rhythm of these genes was determined by serum shock with sodium bromide or equal amounts of sodium chloride. Results Bromide modestly affects cell viability and apoptosis of H9C2 cardiomyocytes. Bromide dampens the clock and glycolytic ( Hk2 and Pkm2 ) gene expression rhythmicity in a dose-dependent manner. Additionally, bromide inhibits autophagic process in H9C2 cardiomyocytes. In contrast, rapamycin (an autophagy inducer) dramatically restores the inhibitory effect of NaBr on the mRNA expression levels of clock genes ( Bmal1 , Cry1 and Rorα ) and glycolytic genes ( Hk2 and Pkm2 ). Conclusions Our results reveal that bromide represses the clock and glycolytic gene expression patterns, partially through inhibition of autophagy.

scholarly journals Platelet-activating factor stimulates gene expression and synthesis of matrix proteins in cultured rat and human mesangial cells: role of TGF-beta.

1997 ◽  
Vol 8 (8) ◽  
pp. 1266-1275
Author(s):  
M Ruiz-Ortega ◽  
R Largo ◽  
C Bustos ◽  
D Gómez-Garre ◽  
J Egido
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Mesangial Cells ◽  
Platelet Activating Factor ◽  
Matrix Proteins ◽  
Type I ◽  
Dependent Manner ◽  
Tgf Beta ◽  
Human Mesangial Cells

Platelet-activating factor (PAF) is a potent inflammatory mediator that participates in the pathogenesis of proteinuria and glomerular damage. However, the role of this lipid in glomerular sclerosis remains unknown. This study examines the effect of PAF on the regulation of extracellular matrix proteins by rat and human mesangial cells. PAF increased in a dose-dependent manner the gene expression of fibronectin and type IV collagen, but not type I collagen. Moreover, an increase in cell-associated and soluble fibronectin synthesis was also seen. These effects were abolished by BN52021 and WEB2086, two different PAF receptor antagonists. Because transforming growth factor (TGF)-beta has been considered a profibrogenic cytokine, this study also evaluated whether PAF effects might be mediated by the production of endogenous TGF-beta. PAF caused an increase in TGF-beta1 mRNA expression (by a protein kinase C-dependent pathway) and TGF-beta activity. Moreover, PAF-induced fibronectin synthesis was totally abolished when an anti-TGF-beta-neutralizing antibody was added to the culture medium, suggesting that PAF stimulates fibronectin synthesis, at least in part, through the induction of TGF-beta. Addition of cycloheximide, a protein synthesis inhibitor, upregulated PAF-induced fibronectin mRNA expression but downregulated PAF-induced TGF-beta1 gene expression, suggesting the existence of different regulatory transcriptional factors of the two proteins. These results suggest that PAF may be implicated in matrix accumulation during renal injury and therefore contribute to the pathogenesis of glomerulosclerosis.

Sign in / Sign up

Export Citation Format

Share Document