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Diabetologia
Published in: Diabetologia 2/2007

01-02-2007 | Article

Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice

Authors: F. Y. Chow, D. J. Nikolic-Paterson, F. Y. Ma, E. Ozols, B. J. Rollins, G. H. Tesch

Published in: Diabetologia | Issue 2/2007

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Abstract

Aims/hypothesis

Tissue macrophage accumulation is thought to induce insulin resistance during obesity and stimulate the progression of diabetic nephropathy. Monocyte chemoattractant protein-1 (MCP-1) is a potent stimulator of macrophage recruitment. It is increased in adipose tissue during obesity and in diabetic kidneys, suggesting that inflammation of these tissues may be MCP-1-dependent. Based on these findings, the aim of this study was to examine whether a deficiency in MCP-1 would alter the development of type 2 diabetes and its renal complications.

Materials and methods

The role of MCP-1 in the progression of type 2 diabetes and its associated renal injury was assessed in obese db/db mice that were deficient in the gene encoding MCP-1 (Ccl2).

Results

The incidence and development of type 2 diabetes were similar in Ccl2 +/+ and Ccl2 −/− db/db mice between 8 and 32 weeks of age. Body mass, hyperglycaemia, hyperinsulinaemia, glucose and insulin tolerance, plasma triacylglycerol and serum NEFA were not different between these strains. Pathological changes in epididymal adipose tissue, including increases in macrophage accumulation and Tnfa mRNA and reductions in Adipoq mRNA, were unaffected by the absence of MCP-1. In contrast, kidney macrophage accumulation and the progression of diabetic renal injury (albuminuria, histopathology, renal fibrosis) were substantially reduced in Ccl2 −/− compared with Ccl2 +/+ db/db mice with equivalent diabetes.

Conclusions/interpretation

Our study demonstrates that MCP-1 promotes type 2 diabetic renal injury but does not influence the development of obesity, insulin resistance or type 2 diabetes in db/db mice. MCP-1 plays a critical role in inflammation of the kidney, but not adipose tissue, during the progression of type 2 diabetes.
Literature
1.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808PubMedCrossRef
2.
Xu H, Barnes GT, Yang Q et al (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830PubMedCrossRef
3.
Furuta T, Saito T, Ootaka T et al (1993) The role of macrophages in diabetic glomerulosclerosis. Am J Kidney Dis 21:480–485PubMed
4.
Chow F, Ozols E, Nikolic-Paterson DJ, Atkins RC, Tesch GH (2004) Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney Int 65:116–128PubMedCrossRef
5.
Weisberg SP, Hunter D, Huber R et al (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116:115–124PubMedCrossRef
6.
Feinstein R, Kanety H, Papa MZ, Lunenfeld B, Karasik A (1993) Tumor necrosis factor-α suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J Biol Chem 268:26055–26058PubMed
7.
Stephens JM, Lee JL, Pilch PF (1997) Tumor necrosis factor-α-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and glut4 expression without loss of insulin receptor-mediated signal transduction. J Biol Chem 272:971–976PubMedCrossRef
8.
Perreault M, Marette A (2001) Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat Med 7:1138–1143PubMedCrossRef
9.
Arkan MC, Hevener AL, Greten FR et al (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198PubMedCrossRef
10.
Chow FY, Nikolic-Paterson DJ, Atkins RC, Tesch GH (2004) Macrophages in streptozotocin-induced diabetic nephropathy: potential role in renal fibrosis. Nephrol Dial Transplant 19:2987–2996PubMedCrossRef
11.
Chow FY, Nikolic-Paterson DJ, Ozols E, Atkins RC, Tesch GH (2005) ICAM-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice. J Am Soc Nephrol 16:1711–1722PubMedCrossRef
12.
Tesch GH, Maifert S, Schwarting A, Rollins BJ, Kelley VR (1999) MCP-1 dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Faslpr mice. J Exp Med 190:1813–1824PubMedCrossRef
13.
Biswas SK, Sodhi A, Paul S (2001) Regulation of nitric oxide production by murine peritoneal macrophages treated in vitro with chemokine monocyte chemoattractant protein 1. Nitric Oxide 5:566–579PubMedCrossRef
14.
Biswas SK, Sodhi A (2002) In vitro activation of murine peritoneal macrophages by monocyte chemoattractant protein-1: upregulation of CD11b, production of proinflammatory cytokines, and the signal transduction pathway. J Interferon Cytokine Res 22:527–538PubMedCrossRef
15.
Sartipy P, Loskutoff DJ (2003) Monocyte chemoattractant protein-1 in obesity and insulin resistance. Proc Natl Acad Sci USA 100:7265–7270PubMedCrossRef
16.
Takahashi K, Mizuarai S, Araki H et al (2003) Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice. J Biol Chem 278:46654–46660PubMedCrossRef
17.
Gerhardt CC, Romero IA, Cancello R, Camoin L, Strosberg AD (2001) Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Mol Cell Endocrinol 175:81–92PubMedCrossRef
18.
Banba N, Nakamura T, Matsumura M, Kuroda H, Hattori Y, Kasai K (2000) Possible relationship of monocyte chemoattractant protein-1 with diabetic nephropathy. Kidney Int 58:684–690PubMedCrossRef
19.
Amann B, Tinzmann R, Angelkort B (2003) ACE inhibitors improve diabetic nephropathy through suppression of renal MCP-1. Diabetes Care 26:2421–2425PubMedCrossRef
20.
Morii T, Fujita H, Narita T et al (2003) Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy. J Diabetes Complications 17:11–15PubMedCrossRef
21.
Lu B, Rutledge BJ, Gu L et al (1998) Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med 187:601–608PubMedCrossRef
22.
Kumar S, McCue P, Dunn SR (2003) Diabetic kidney disease in the db/db mouse. Am J Physiol Renal Physiol 284:F1138–F1144
23.
van den Berg TK, van Die I, de Lavalette CR et al (1996) Regulation of sialoadhesin expression on rat macrophages. Induction by glucocorticoids and enhancement by IFN-beta, IFN-gamma, IL-4 and lipopolysaccharide. J Immunol 157:3130–3138PubMed
24.
Chow FY, Nikolic-Paterson DJ, Ozols E, Atkins RC, Rollins BJ, Tesch GH (2006) Monocyte chemoattractant protein-1 promotes diabetic renal injury in streptozotocin-treated mice. Kidney Int 69:73–80PubMedCrossRef
25.
Masaki T, Chow F, Nikolic-Paterson DJ, Atkins RC, Tesch GH (2003) Heterogeneity of antigen expression explains controversy over glomerular macrophage accumulation in mouse glomerulonephritis. Nephrol Dial Transplant 18:178–181PubMedCrossRef
26.
Di Gregorio GB, Yao-Borengasser A, Rasouli N et al (2005) Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance and reduction by pioglitazone. Diabetes 54:2305–2313PubMedCrossRef
27.
Kanda H, Tateya S, Tamori Y et al (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116:1494–1505PubMedCrossRef
28.
Kamei N, Tobe K, Suzuki R et al (2006) Overexpression of MCP-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem DOI 10.​1074/​jbc.​M601284200
29.
Brittingham KC, Reynolds JM, Suttles J, Hotamisligil GS (2005) The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities. J Biol Chem 280:12888–12895PubMed
30.
Chen A, Mumick S, Zhang C et al (2005) Diet induction of monocyte chemoattractant protein-1 and its impact on obesity. Obes Res 13:1311–1320PubMed
31.
Skurk T, Herder C, Kraft I, Muller-Scholze S, Haumer H, Kolb H (2005) Production and release of macrophage migration inhibitory factor from human adipocytes. Endocrinology 146:1006–1011PubMedCrossRef
32.
Levine JA, Jensen MD, Eberhardt NL, O’Brien T (1998) Adipocyte macrophage-colony stimulating factor is a mediator of adipose tissue growth. J Clin Invest 101:1557–1564PubMedCrossRef
33.
Le Meur Y, Tesch GH, Hill PA et al (2002) Macrophage accumulation at a site of renal inflammation is dependent on the M-CSF/c-fms pathway. J Leuk Biol 72:530–537
Metadata
Title
Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice
Authors
F. Y. Chow
D. J. Nikolic-Paterson
F. Y. Ma
E. Ozols
B. J. Rollins
G. H. Tesch
Publication date
01-02-2007
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 2/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-006-0497-8

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