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The roles of Kruppel-like factor 6 and peroxisome proliferator-activated receptor-γ in the regulation of macrophage inflammatory protein-3α at early onset of diabetes.
Int J Biochem Cell Biol. 2011 Mar; 43(3):383-92.IJ

Abstract

Macrophage inflammatory protein-3 alpha (MIP-3α) is known to be upregulated early in the development of diabetic nephropathy (DN). However, the transcriptional regulation of MIP-3α is unknown. We previously demonstrated that the transcription factors KLF6 and PPAR-γ play key roles in regulating renal fibrotic and inflammatory responses to factors inherent in diabetes mellitus. Hence we determined the role of these transcription factors in regulating MIP-3α expression. HK-2 cells and STZ-induced diabetic rats were used. siRNAs, over-expressing constructs and CHIP promoter binding assays were used to determine the role of KLF6 and PPAR-γ in MIP-3α transcriptional regulation. KLF6 overexpression increased MIP-3α which was inhibited by concurrent exposure to PPAR-γ agonists. PPAR-γ agonists attenuated high glucose-induced MIP-3α secretion. Furthermore, MIP-3α secretion was up-regulated in PPAR-γ silenced cells, suggesting both KLF6 and PPAR-γ antagonistically regulate high glucose-induced MIP-3α secretion. The CHIP promoter binding assay confirmed that PPAR-γ binds to the MIP-3α promoter and negatively regulates MIP-3α expression. PPAR-γ agonists increased the binding activity of the PPAR-γ-MIP-3α promoter. In contrast, promoter binding activity decreased in KLF6 over-expressing cells. PPAR-γ decreased in KLF6 over-expressing cells and increased in KLF6 silenced cells, while PPAR-γ siRNA had no effect on KLF6 expression, suggesting that KLF6 acted upstream of PPAR-γ in the regulation of MIP-3α. In diabetic rats, renal MIP-3α and the macrophage marker ED-1 expression increased, which was inhibited by exposure to PPAR-γ agonists. The recognition of MIP-3α as a significant pathogenic mediator in diabetic nephropathy reaffirms the increasingly recognized role of inflammation in the progression of DN. Targeting pro-inflammatory chemokine MIP-3α and its signaling pathways will provide novel strategy to treat diabetic kidney disease.

Authors+Show Affiliations

Kolling Institute, Dept of Medicine, Royal North Shore Hospital, University of Sydney, Sydney, Australia. wqi@med.usyd.edu.auNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21109018

Citation

Qi, Weier, et al. "The Roles of Kruppel-like Factor 6 and Peroxisome Proliferator-activated Receptor-γ in the Regulation of Macrophage Inflammatory Protein-3α at Early Onset of Diabetes." The International Journal of Biochemistry & Cell Biology, vol. 43, no. 3, 2011, pp. 383-92.
Qi W, Holian J, Tan CY, et al. The roles of Kruppel-like factor 6 and peroxisome proliferator-activated receptor-γ in the regulation of macrophage inflammatory protein-3α at early onset of diabetes. Int J Biochem Cell Biol. 2011;43(3):383-92.
Qi, W., Holian, J., Tan, C. Y., Kelly, D. J., Chen, X. M., & Pollock, C. A. (2011). The roles of Kruppel-like factor 6 and peroxisome proliferator-activated receptor-γ in the regulation of macrophage inflammatory protein-3α at early onset of diabetes. The International Journal of Biochemistry & Cell Biology, 43(3), 383-92. https://doi.org/10.1016/j.biocel.2010.11.008
Qi W, et al. The Roles of Kruppel-like Factor 6 and Peroxisome Proliferator-activated Receptor-γ in the Regulation of Macrophage Inflammatory Protein-3α at Early Onset of Diabetes. Int J Biochem Cell Biol. 2011;43(3):383-92. PubMed PMID: 21109018.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The roles of Kruppel-like factor 6 and peroxisome proliferator-activated receptor-γ in the regulation of macrophage inflammatory protein-3α at early onset of diabetes. AU - Qi,Weier, AU - Holian,John, AU - Tan,Christina Y R, AU - Kelly,Darren J, AU - Chen,Xin-Ming, AU - Pollock,Carol A, Y1 - 2010/11/23/ PY - 2010/08/07/received PY - 2010/11/11/revised PY - 2010/11/16/accepted PY - 2010/11/27/entrez PY - 2010/11/27/pubmed PY - 2011/5/19/medline SP - 383 EP - 92 JF - The international journal of biochemistry & cell biology JO - Int J Biochem Cell Biol VL - 43 IS - 3 N2 - Macrophage inflammatory protein-3 alpha (MIP-3α) is known to be upregulated early in the development of diabetic nephropathy (DN). However, the transcriptional regulation of MIP-3α is unknown. We previously demonstrated that the transcription factors KLF6 and PPAR-γ play key roles in regulating renal fibrotic and inflammatory responses to factors inherent in diabetes mellitus. Hence we determined the role of these transcription factors in regulating MIP-3α expression. HK-2 cells and STZ-induced diabetic rats were used. siRNAs, over-expressing constructs and CHIP promoter binding assays were used to determine the role of KLF6 and PPAR-γ in MIP-3α transcriptional regulation. KLF6 overexpression increased MIP-3α which was inhibited by concurrent exposure to PPAR-γ agonists. PPAR-γ agonists attenuated high glucose-induced MIP-3α secretion. Furthermore, MIP-3α secretion was up-regulated in PPAR-γ silenced cells, suggesting both KLF6 and PPAR-γ antagonistically regulate high glucose-induced MIP-3α secretion. The CHIP promoter binding assay confirmed that PPAR-γ binds to the MIP-3α promoter and negatively regulates MIP-3α expression. PPAR-γ agonists increased the binding activity of the PPAR-γ-MIP-3α promoter. In contrast, promoter binding activity decreased in KLF6 over-expressing cells. PPAR-γ decreased in KLF6 over-expressing cells and increased in KLF6 silenced cells, while PPAR-γ siRNA had no effect on KLF6 expression, suggesting that KLF6 acted upstream of PPAR-γ in the regulation of MIP-3α. In diabetic rats, renal MIP-3α and the macrophage marker ED-1 expression increased, which was inhibited by exposure to PPAR-γ agonists. The recognition of MIP-3α as a significant pathogenic mediator in diabetic nephropathy reaffirms the increasingly recognized role of inflammation in the progression of DN. Targeting pro-inflammatory chemokine MIP-3α and its signaling pathways will provide novel strategy to treat diabetic kidney disease. SN - 1878-5875 UR - https://www.unboundmedicine.com/medline/citation/21109018/The_roles_of_Kruppel_like_factor_6_and_peroxisome_proliferator_activated_receptor_γ_in_the_regulation_of_macrophage_inflammatory_protein_3α_at_early_onset_of_diabetes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1357-2725(10)00386-9 DB - PRIME DP - Unbound Medicine ER -