| Cystathionine β-synthase and cystathionine γ-lyase double gene transfer ameliorate homocysteine-mediated mesangial inflammation through hydrogen sulfide generation. | |
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MedLine Citation:
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PMID: 20943958 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Elevated level of homocysteine (Hcy) induces chronic inflammation in vascular bed, including glomerulus, and promotes glomerulosclerosis. In this study we investigated in vitro mechanism of Hcy-mediated monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) induction and determined the regulatory role of hydrogen sulfide (H₂S) to ameliorate inflammation. Mouse glomerular mesangial cells (MCs) were incubated with Hcy (75 μM) and supplemented with vehicle or with H₂S (30 μM, in the form of NaHS). Inflammatory molecules MCP-1 and MIP-2 were measured by ELISA. Cellular capability to generate H₂S was measured by colorimetric chemical method. To enhance endogenous production of H₂S and better clearance of Hcy, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) genes were delivered to the cells. Oxidative NAD(P)H p47(phox) was measured by Western blot analysis and immunostaining. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH₂-terminal kinase (JNK1/2) were measured by Western blot analysis. Our results demonstrated that Hcy upregulated inflammatory molecules MCP-1 and MIP-2, whereas endogenous production of H₂S was attenuated. H₂S treatment as well as CBS and CSE doubly cDNA overexpression markedly reduced Hcy-induced upregulation of MCP-1 and MIP-2. Hcy-induced upregulation of oxidative p47(phox) was attenuated by H₂S supplementation and CBS/CSE overexpression as well. In addition to that we also detected Hcy-induced MCP-1 and MIP-2 induction was through phosphorylation of ERK1/2 and JNK1/2. Either H₂S supplementation or CBS and CSE doubly cDNA overexpression attenuated Hcy-induced phosphorylation of these two signaling molecules and diminished MCP-1 and MIP-2 expressions. Similar results were obtained by inhibition of ERK1/2 and JNK1/2 using pharmacological and small interferring RNA (siRNA) blockers. We conclude that H₂S plays a regulatory role in Hcy-induced mesangial inflammation and that ERK1/2 and JNK1/2 are two signaling pathways involved this process. |
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Authors:
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Utpal Sen; Srikanth Givvimani; Oluwasegun A Abe; Eleanor D Lederer; Suresh C Tyagi |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-10-13 |
Journal Detail:
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Title: American journal of physiology. Cell physiology Volume: 300 ISSN: 1522-1563 ISO Abbreviation: Am. J. Physiol., Cell Physiol. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-29 Completed Date: 2011-02-04 Revised Date: 2012-01-02 |
Medline Journal Info:
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Nlm Unique ID: 100901225 Medline TA: Am J Physiol Cell Physiol Country: United States |
Other Details:
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Languages: eng Pagination: C155-63 Citation Subset: IM |
Affiliation:
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Department of Physiology & Biophysics, University of Louisville, KY 40202, USA. u0sen001@louisville.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cells, Cultured Chemokine CCL2 / genetics, metabolism Chemokine CXCL2 / genetics, metabolism Cystathionine beta-Synthase / genetics, metabolism* Cystathionine gamma-Lyase / genetics, metabolism* Extracellular Signal-Regulated MAP Kinases / genetics, metabolism Gene Expression Regulation / physiology Homocysteine / metabolism* Hydrogen Sulfide / metabolism* Inflammation / metabolism, pathology* JNK Mitogen-Activated Protein Kinases / genetics, metabolism Mesangial Cells / metabolism* Mice Signal Transduction / physiology |
| Grant Support | |
ID/Acronym/Agency:
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HL-71010/HL/NHLBI NIH HHS; HL-88012/HL/NHLBI NIH HHS; NS-51568/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Ccl2 protein, mouse; 0/Chemokine CCL2; 0/Chemokine CXCL2; 0/Cxcl2 protein, mouse; 454-28-4/Homocysteine; 7783-06-4/Hydrogen Sulfide; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 4.2.1.22/Cystathionine beta-Synthase; EC 4.4.1.1/Cystathionine gamma-Lyase |
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