Inhibition of MCP-1/CCR2 pathway ameliorates the development of diabetic nephropathy

Kanamori, Hiroshi; Matsubara, Takeshi; Mima, Akira; Sumi, Eriko; Nagai, Kojiro; Takahashi, Tomohiro; Abe, Hideharu; Iehara, Noriyuki; Fukatsu, Atsushi; Okamoto, Hiroshi; Kita, Toru; Doi, Toshio; Arai, Hidenori

doi:10.1016/j.bbrc.2007.06.148

Cited by 156 publications

(114 citation statements)

References 22 publications

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“…The macrophage has been presumed to be a critical mediator of diabetic nephropathy [36][37][38], and blockade of the MCP-1/CC chemokine receptor 2 system in diabetic mice leads to reduced albuminuria, mesangial expansion and macrophage infiltration [39][40][41][42]. Secretory factors from macrophages may cause histological and functional changes in glomeruli.…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

et al. 2012

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Aims/hypothesis Hyperlipidaemia is an independent risk factor for the progression of diabetic nephropathy, but its molecular mechanism remains elusive. We investigated in mice how diabetes and hyperlipidaemia cause renal lesions separately and in combination, and the involvement of Toll-like receptor 4 (TLR4) in the process. Methods Diabetes was induced in wild-type (WT) and Tlr4 knockout (KO) mice by intraperitoneal injection of streptozotocin (STZ). At 2 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Functional and histological analyses were carried out 6 weeks later. Results Compared with treatment with STZ or HFD alone, treatment of WT mice with both STZ and HFD markedly aggravated nephropathy, as indicated by an increase in albuminuria, mesangial expansion, infiltration of macrophages and upregulation of pro-inflammatory and extracellularmatrix-associated gene expression in glomeruli. In Tlr4 KO mice, the addition of an HFD to STZ had almost no effects on the variables measured. Production of protein S100 calcium binding protein A8 (calgranulin A; S100A8), a potent ligand for TLR4, was observed in abundance in macrophages infiltrating STZ-HFD WT glomeruli and in glomeruli of diabetic nephropathy patients. High-glucose and fatty acid treatment synergistically upregulated S100a8 gene expression in macrophages from WT mice, but not from KO mice. As putative downstream targets of TLR4, phosphorylation of interferon regulatory factor 3 (IRF3) was enhanced in kidneys of WT mice co-treated with STZ and HFD. Conclusions/interpretation Activation of S100A8/TLR4 signalling was elucidated in an animal model of diabetic glomerular injury accompanied with hyperlipidaemia, which may provide novel therapeutic targets in progressive diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

et al. 2012

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“…In fact, disruption of the CCR2 pathway has already been considered for the treatment of atherosclerosis, inflammation, rheumatoid arthritis and multiple sclerosis [32]. In addition, several pre-clinical studies also have shown promise for CCR2 inhibition including protective effects on diabetic nephropathy [33], renal fibrosis [31], and high-fat diet-induced insulin resistance and glucose intolerance [17]. However, it is worth noting that the complete absence of CCR2 probably has detrimental effects.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the chemokine (C–C motif) ligand 2/chemokine (C–C motif) receptor 2 pathway attenuates hyperglycaemia and inflammation in a mouse model of hepatic steatosis and lipoatrophy

et al. 2009

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Aims/hypothesis Using a mouse model of lipoatrophic diabetes, we hypothesised that the chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-C motif) receptor 2 (CCR2) pathway contributes to hepatic macrophage accumulation and insulin resistance through induction of a chronic inflammatory state. Methods Metabolic variables of insulin resistance and inflammation were characterised in wild-type and lipoatrophic A-ZIP/F-1 transgenic (AZIP-Tg) mice. The AZIP-Tg mice were then treated with a CCR2 antagonist (RS504393, 2 mg kg −1 day −1 ) or vehicle for 28 days via a subcutaneous mini-osmotic pump to examine the role of the CCL2/CCR2 pathway in lipoatrophic diabetes.Results The lipoatrophic AZIP-Tg mice were diabetic with high fasting glucose and serum insulin concentrations compared with littermate controls. The livers of AZIP-Tg mice were more than threefold enlarged and exhibited increased triacylglycerol content. CCL2 levels were highly elevated in both liver and serum of the AZIP-Tg mice compared with controls. In addition, the circulating CCL2 concentration was associated with increased macrophage accumulation and inflammation as documented by upregulation of Cd68 gene and Tnf-α [also known as Tnf] gene in livers from the AZIP-Tg mice. Treatment of the lipoatrophic AZIP-Tg mice with the CCR2 antagonist ameliorated the hyperglycaemia, hyperinsulinaemia and hepatomegaly in conjunction with a reduction in liver inflammation. Conclusions/interpretation These findings demonstrate a significant role of the CCL2/CCR2 pathway in lipoatrophy-induced diabetes and provide clear evidence that metabolic improvements resulting from the inhibition of this inflammatory pathway are not adipose tissuedependent.

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“…Similarly, genetic deficiency of molecules facilitating leucocyte recruitment (e.g. Icam1, Ccl2) and pharmacological blockade of chemokine CC motif receptors (CCR) 1 and 2 can reduce macrophage accumulation and renal injury in mouse models of diabetic nephropathy [6,[9][10][11][12]. However, these approaches are limited in that they do not target macrophages selectively, restricting the interpretation of these findings.…”

Section: Introductionmentioning

confidence: 99%

Antibody blockade of c-fms suppresses the progression of inflammation and injury in early diabetic nephropathy in obese db/db mice

Lim

Nikolic‐Paterson

et al. 2009

Diabetologia

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Aims/hypothesis Macrophage-mediated renal injury plays an important role in the development of diabetic nephropathy. Colony-stimulating factor (CSF)-1 is a cytokine that is produced in diabetic kidneys and promotes macrophage accumulation, activation and survival. CSF-1 acts exclusively through the c-fms receptor, which is only expressed on cells of the monocyte-macrophage lineage. Therefore, we used c-fms blockade as a strategy to selectively target macrophage-mediated injury during the progression of diabetic nephropathy. Methods Obese, type 2 diabetic db/db BL/KS mice with established albuminuria were treated with a neutralising anti-c-fms monoclonal antibody (AFS98) or isotype matched control IgG from 12 to 18 weeks of age and examined for renal injury. Results Treatment with AFS98 did not affect obesity, hyperglycaemia, circulating monocyte levels or established albuminuria in db/db mice. However, AFS98 did prevent glomerular hyperfiltration and suppressed variables of inflammation in the diabetic kidney, including kidney macrophages (accumulation, activation and proliferation), chemokine CC motif ligand 2 levels (mRNA and urine protein), kidney activation of proinflammatory pathways (c-Jun amino-terminal kinase and activating transcription factor 2) and Tnf-α (also known as Tnf) mRNA levels. In addition, AFS98 decreased the tissue damage caused by macrophages including tubular injury (apoptosis and hypertrophy), interstitial damage (cell proliferation and myofibroblast accrual) and renal fibrosis (Tgf-β1 [also known as Tgfb1] and Col4a1 mRNA). Conclusions/interpretation Blockade of c-fms can suppress the progression of established diabetic nephropathy in db/db mice by targeting macrophage-mediated injury.

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Inhibition of MCP-1/CCR2 pathway ameliorates the development of diabetic nephropathy

Cited by 156 publications

References 22 publications

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

Inhibition of the chemokine (C–C motif) ligand 2/chemokine (C–C motif) receptor 2 pathway attenuates hyperglycaemia and inflammation in a mouse model of hepatic steatosis and lipoatrophy

Antibody blockade of c-fms suppresses the progression of inflammation and injury in early diabetic nephropathy in obese db/db mice

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