MCP-1/CCR2 system is involved in high glucose-induced fibronectin and type IV collagen expression in cultured mesangial cells.

Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that plays an important role in the recruitment of macrophages. Although previous studies have demonstrated the importance of MCP-1 in the pathogenesis of diabetic nephropathy (DN) in terms of inflammation, the role of MCP-1 and its receptor (C-C chemokine receptor 2; CCR2) in extracellular matrix (ECM) accumulation under diabetic conditions has been largely unexplored. This study was undertaken to investigate the functional role of the MCP-1/CCR2 system in high glucose-induced ECM (fibronectin and type IV collagen) protein expression in cultured mesangial cells (MCs). Mouse MCs were exposed to medium containing 5.6 mM glucose (NG), NG+24.4 mM mannitol (NG+M), or 30 mM glucose (HG) with or without mutant MCP-1 (mMCP-1), CCR2 small interfering (si)RNA, or CCR2 inhibitor (RS102895). To examine the relationship between MCP-1 and transforming growth factor (TGF)-beta1, MCs were also treated with TGF-beta1 (2 ng/ml) with or without mMCP-1 or CCR2 siRNA. Transient transfection was performed with Lipofectamine 2000 for 24 h. Cell viability was determined by an MTT assay, mouse and human MCP-1 and TGF-beta1 levels by ELISA, and CCR2 and ECM protein expression by Western blotting. Transfections of mMCP-1 and CCR2 siRNA increased human MCP-1 levels and inhibited CCR2 expression, respectively. HG-induced ECM protein expression and TGF-beta1 levels were significantly attenuated by mMCP-1, CCR2 siRNA, and RS102895 (P < 0.05). MCP-1 directly increased ECM protein expression, and this increase was inhibited by an anti-TGF-beta1 antibody. In addition, TGF-beta1-induced ECM protein expression was significantly abrogated by the inhibition of the MCP-1/CCR2 system (P < 0.05). These results suggest that an interaction between the MCP-1/CCR2 system and TGF-beta1 may contribute to ECM accumulation in DN.

[1]  M. Cooper,et al.  Monocyte chemoattractant protein-1 has prosclerotic effects both in a mouse model of experimental diabetes and in vitro in human mesangial cells , 2007, Diabetologia.

[2]  S. Maggirwar,et al.  Pneumocystis stimulates MCP-1 production by alveolar epithelial cells through a JNK-dependent mechanism. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[3]  T. Muneta,et al.  Transforming growth factor-β stimulates IL-1β-induced monocyte chemoattractant protein-1 expression in human synovial cells via the ERK/AP-1 pathway , 2006, Inflammation Research.

[4]  D. Cha,et al.  Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. , 2006, Journal of the American Society of Nephrology : JASN.

[5]  G. Camussi,et al.  The MCP-1/CCR2 system has direct proinflammatory effects in human mesangial cells. , 2006, Kidney international.

[6]  R. Gilbert,et al.  TGF-beta1 induces IL-8 and MCP-1 through a connective tissue growth factor-independent pathway. , 2006, American journal of physiology. Renal physiology.

[7]  D. Busch,et al.  Chemokine receptor Ccr2 deficiency reduces renal disease and prolongs survival in MRL/lpr lupus-prone mice. , 2005, Journal of the American Society of Nephrology : JASN.

[8]  D. Sugden,et al.  Mechanical stretch induces monocyte chemoattractant activity via an NF-kappaB-dependent monocyte chemoattractant protein-1-mediated pathway in human mesangial cells: inhibition by rosiglitazone. , 2005, Journal of the American Society of Nephrology : JASN.

[9]  K. Matsushima,et al.  Blockade of CCR2 ameliorates progressive fibrosis in kidney. , 2004, The American journal of pathology.

[10]  Yasunori Iwata,et al.  Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. , 2004, Journal of the American Society of Nephrology : JASN.

[11]  K. Matsushima,et al.  Gene therapy expressing amino-terminal truncated monocyte chemoattractant protein-1 prevents renal ischemia-reperfusion injury. , 2003, Journal of the American Society of Nephrology : JASN.

[12]  U. Panzer,et al.  Existence of a regulatory loop between MCP-1 and TGF-beta in glomerular immune injury. , 2002, American journal of physiology. Renal physiology.

[13]  F. Cipollone,et al.  Circulating monocyte chemoattractant protein-1 and early development of nephropathy in type 1 diabetes. , 2002, Diabetes care.

[14]  A. Phillips,et al.  Differential Expression of Mcp-1 and Its Receptor CCR2 in Glucose Primed Human Mesangial Cells , 2002, Nephron.

[15]  G. Lin,et al.  Upregulation of monocyte chemoattractant protein 1 and effects of transforming growth factor-beta 1 in Peyronie's disease. , 2002, Biochemical and biophysical research communications.

[16]  Z. Makita,et al.  Advanced Glycation End Product-induced Apoptosis and Overexpression of Vascular Endothelial Growth Factor and Monocyte Chemoattractant Protein-1 in Human-cultured Mesangial Cells* , 2002, The Journal of Biological Chemistry.

[17]  D. Figarella-Branger,et al.  CCR2A and CCR2B, the two isoforms of the monocyte chemoattractant protein-1 receptor are up-regulated and expressed by different cell subsets in idiopathic inflammatory myopathies , 2001, Acta Neuropathologica.

[18]  S. Sanders,et al.  Functional Differences Between Monocyte Chemotactic Protein-1 Receptor A and Monocyte Chemotactic Protein-1 Receptor B Expressed in a Jurkat T Cell , 2000, The Journal of Immunology.

[19]  K. Matsushima,et al.  Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy. , 2000, Kidney international.

[20]  Y. Hattori,et al.  Possible relationship of monocyte chemoattractant protein-1 with diabetic nephropathy. , 2000, Kidney international.

[21]  D. Heudes,et al.  Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. , 2000, Diabetes.

[22]  B. Brenner,et al.  Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats. , 1999, Kidney international.

[23]  F. Thaiss,et al.  Monocyte chemoattractant protein-1 mediates collagen deposition in experimental glomerulonephritis by transforming growth factor-β , 1999 .

[24]  C. Martínez-A,et al.  The chemokine monocyte chemoattractant protein-1 induces functional responses through dimerization of its receptor CCR2. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Egido,et al.  Angiotensin II participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor-kappa B activation and monocyte chemoattractant protein-1 synthesis. , 1998, Journal of immunology.

[26]  Jae-Kyung Park,et al.  A High Glucose Concentration Stimulates the Expression of Monocyte Chemotactic Peptide 1 in Human Mesangial Cells , 1998, Nephron.

[27]  K. Sharma,et al.  Potential Role of TGF-β in Diabetic Nephropathy , 1998, Mineral and Electrolyte Metabolism.

[28]  M. Daha,et al.  Production and cytokine-mediated regulation of monocyte chemoattractant protein-1 by human proximal tubular epithelial cells. , 1995, Kidney international.

[29]  C. Alpers,et al.  Cellular events in the evolution of experimental diabetic nephropathy. , 1995, Kidney international.

[30]  B. Rollins,et al.  Structure/activity analysis of human monocyte chemoattractant protein-1 (MCP-1) by mutagenesis. Identification of a mutated protein that inhibits MCP-1-mediated monocyte chemotaxis. , 1994, The Journal of biological chemistry.

[31]  S. Coughlin,et al.  Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[32]  K. Yoshinaga,et al.  The role of macrophages in diabetic glomerulosclerosis. , 1993, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[33]  B. Rovin,et al.  Cytokine-induced production of monocyte chemoattractant protein-1 by cultured human mesangial cells. , 1992, Journal of immunology.

[34]  P. Ward,et al.  Evidence for the role of oxygen radicals in acute nephrotoxic nephritis. , 1984, Laboratory investigation; a journal of technical methods and pathology.

[35]  A. Mitra.  Diabetes , 1894, The Indian medical gazette.

[36]  R. Atkins,et al.  Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice. , 2006, Kidney international.

[37]  R. Atkins,et al.  Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. , 2004, Kidney international.

[38]  M. Kakei,et al.  Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy. , 2003, Journal of diabetes and its complications.

[39]  S. Segerer,et al.  Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies. , 2000, Journal of the American Society of Nephrology : JASN.

[40]  K. Matsushima,et al.  J Am Soc Nephrol 14: 2503–2515, 2003 CCR2 Signaling Contributes to Ischemia-Reperfusion Injury , 2022 .

[41]  Y. Yuzawa,et al.  J Am Soc Nephrol 14: 1496–1505, 2003 Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Renal Injury Induced by Protein-Overload , 2022 .