A Novel C–C Chemokine Receptor 2 Antagonist Prevents Progression of Albuminuria and Atherosclerosis in Mouse Models

Okamoto, Masayuki; Fuchigami, Masahiro; Suzuki, Takeshi; Watanabe, Nozomi

doi:10.1248/bpb.b12-00528

Cited by 35 publications

(27 citation statements)

References 47 publications

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“…To interrupt the CCL2-CCR2 axis, several types of inhibitors such as CCR2 antagonist, neutralizing antibody of CCL2, CCL2 mutant protein with property of inhibiting CCL2 singling and RNA interference technology have been investigated for treatment of cardiovascular disease, neurodegenerative disease, cancer, and chronic inflammatory diseases [24, 40–44]. Our previous studies [16–18] and the current study demonstrate the positive effects of 7ND, a dominant negative mutant CCL2, on mitigating wear particle-induced bone loss.…”

Section: Discussionmentioning

confidence: 99%

Mutant CCL2 protein coating mitigates wear particle-induced bone loss in a murine continuous polyethylene infusion model

et al. 2017

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Wear particle-induced osteolysis limits the long-term survivorship of total joint replacement (TJR). Monocyte/macrophages are the key cells of this adverse reaction. Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) is the most important chemokine regulating trafficking of monocyte/macrophages in particle-induced inflammation. 7ND recombinant protein is a mutant of CCL2 that inhibits CCL2 signaling. We have recently developed a layer-by-layer (LBL) coating platform on implant surfaces that can release biologically active 7ND. In this study, we investigated the effect of 7ND on wear particle-induced bone loss using the murine continuous polyethylene (PE) particle infusion model with 7ND coating of a titanium rod as a local drug delivery device. PE particles were infused into hollow titanium rods with or without 7ND coating implanted in the distal femur for 4 weeks. Specific groups were also injected with RAW 264.7 as the reporter macrophages. Wear particle-induced bone loss and the effects of 7ND were evaluated by microCT, immunohistochemical staining, and bioluminescence imaging. Local delivery of 7ND using the LBL coating decreased systemic macrophage recruitment, the number of osteoclasts and wear particle-induced bone loss. The development of a novel orthopaedic implant coating with anti-CCL2 protein may be a promising strategy to mitigate peri-prosthetic osteolysis.

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Section: Discussionmentioning

confidence: 99%

Mutant CCL2 protein coating mitigates wear particle-induced bone loss in a murine continuous polyethylene infusion model

et al. 2017

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“…In diabetic nephropathy, there is increased CCL2 expression in the kidney and urine (3,28,29,42) and increased numbers of macrophages in the kidney (14,31). In diabetic leptin receptordeficient (db/db) mice, other CCR2 antagonists have slowed or blocked the increase in albuminuria that occurs over time in these mice, but a reduction in albuminuria relative to disease severity at start of the study has not been demonstrated (22,32,38,41). Here, we show that, in diabetic hCCR2 KI db/db mice, CCX140-B reduced albuminuria within 1 wk of treatment and maintained this benefit over the entire 6-wk treatment period.…”

Section: Discussionmentioning

confidence: 99%

“…Glomerular CCR2 expression is increased in patients with diabetic nephropathy (45). Diabetic mice deficient in CCL2 (9,10,45) or treated with CCR2 antagonists (20,22,32,38) exhibit reduced proteinuria.…”

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confidence: 99%

CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice

Sullivan

Miao

Dairaghi

et al. 2013

American Journal of Physiology-Renal Physiology

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. CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice. Am J Physiol Renal Physiol 305: F1288 -F1297, 2013. First published August 28, 2013 doi:10.1152/ajprenal.00316.2013.-Chemokine (C-C motif) receptor 2 (CCR2) is central for the migration of monocytes into inflamed tissues. The novel CCR2 antagonist CCX140-B, which is currently in two separate phase 2 clinical trials in diabetic nephropathy, has recently been shown to reduce hemoglobin A1c and fasting blood glucose levels in type 2 diabetics. In this report, we describe the effects of this compound on glycemic and renal function parameters in diabetic mice. Since CCX140-B has a low affinity for mouse CCR2, transgenic human CCR2 knockin mice were generated and rendered diabetic with either a high-fat diet (diet-induced obesity) or by deletion of the leptin receptor gene (db/db). CCX140-B treatment in both models resulted in decreased albuminuria, which was associated with decreased glomerular hypertrophy and increased podocyte density. Moreover, treatment of diet-induced obese mice with CCX140-B resulted in decreased levels of fasting blood glucose and insulin, normalization of homeostatic model assessment of insulin resistance values, and decreased numbers of adipose tissue inflammatory macrophages. Unlike other CCR2 antagonists, CCX140-B had no effect on plasma levels of the CCR2 ligand CCL2 or on the numbers of blood monocytes. These results support the ongoing evaluation of this molecule in diabetic subjects with impaired renal function.

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“…CCL2 is closely associated with the process of glomerular and interstitial inflammatory cell recruitment, such as macrophage cells. Hence, the blockade of the CCL-2/CCL-2 receptor (CCR-2) pathway could have considerable therapeutic potential for DN (161).…”

Section: Drugs Targeting Inflammationmentioning

confidence: 99%

Management of diabetic nephropathy: Recent progress and future perspective

Ahmad

2015

Diabetes & Metabolic Syndrome: Clinical Research & Revi

132

102

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A Novel C–C Chemokine Receptor 2 Antagonist Prevents Progression of Albuminuria and Atherosclerosis in Mouse Models

Abstract: In conclusion, the results of this study indicate not only considerable therapeutic potential of CCR2 antagonists for diabetic nephropathy and atherosclerosis, but also that TLK-19705 would serve as a powerful tool in mechanistic investigation of these inflammatory diseases.

Cited by 35 publications

References 47 publications

Mutant CCL2 protein coating mitigates wear particle-induced bone loss in a murine continuous polyethylene infusion model

Mutant CCL2 protein coating mitigates wear particle-induced bone loss in a murine continuous polyethylene infusion model

CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice

Management of diabetic nephropathy: Recent progress and future perspective

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