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Dual CCR2/CCR5 antagonist treatment attenuates adipose inflammation, but not microvascular complications in ob/ob
Phillipe D O'Brien1, Lucy M Hinder1, Sebastian D Parlee2
1Department of Neurology, University of Michigan, Ann Arbor, Michigan.
Abstract:
Diabetic peripheral neuropathy (DPN) and diabetic kidney disease (DKD) are common diabetic complications with limited treatment options. Experimental studies show that targeting inflammation using chemokine receptor (CCR) antagonists ameliorates DKD, presumably by reducing macrophage accumulation or activation. As inflammation is implicated in DPN development, we assessed whether CCR2 and CCR5 antagonism could also benefit DPN. Five-week-old ob/ob mice were fed a diet containing MK-0812, a dual CCR2-CCR5 receptor antagonist, for 8 weeks; DPN, DKD and metabolic phenotyping were then performed to determine the effect of CCR inhibition. Although MK-0812 reduced macrophage accumulation in adipose tissue, the treatment had largely no effect on metabolic parameters, nerve function or kidney disease in ob/ob mice. These results conflict with published data that demonstrate a benefit of CCR antagonists for DKD and hyperglycaemia. We conclude that CCR signaling blockade is ineffective in ob/ob mice and suspect that this is explained by the severe hyperglycaemia found in this model. It remains to be determined whether MK-0812 treatment, alone or in combination with improved glycaemic control, is useful in preventing diabetic complications in alternate animal models.
Insights
Chemokine receptor (CCR) antagonists did not improve nerve or kidney function in diabetic mice, likely due to severe hyperglycemia. Further research is needed to determine their efficacy in other models or with improved glycemic control.
Area of Science:
- Endocrinology
- Immunology
- Nephrology
Background:
- Diabetic peripheral neuropathy (DPN) and diabetic kidney disease (DKD) are significant complications of diabetes with few treatment options.
- Inflammation, particularly macrophage involvement, is implicated in the pathogenesis of DPN and DKD.
- Chemokine receptor (CCR) antagonists have shown promise in ameliorating DKD in experimental models.
Purpose of the Study:
- To investigate the therapeutic potential of CCR2 and CCR5 antagonism for diabetic complications, specifically DPN and DKD.
- To assess the effects of a dual CCR2-CCR5 antagonist (MK-0812) on nerve function, kidney disease, and metabolic parameters in a mouse model of diabetes.
Main Methods:
- Five-week-old ob/ob mice, a model of type 2 diabetes, were treated with MK-0812, a CCR2-CCR5 antagonist, for 8 weeks.
- Comprehensive phenotyping included assessments of DPN, DKD, and metabolic parameters.
- Macrophage accumulation in adipose tissue was evaluated.
Main Results:
- MK-0812 treatment reduced macrophage accumulation in adipose tissue.
- However, the antagonist showed no significant beneficial effect on metabolic parameters, nerve function (DPN), or kidney disease (DKD) in ob/ob mice.
- These findings contrast with previous studies suggesting benefits of CCR antagonists for DKD and hyperglycemia.
Conclusions:
- CCR signaling blockade with MK-0812 was ineffective in ameliorating DPN and DKD in the ob/ob mouse model.
- The lack of efficacy is hypothesized to be due to the severe hyperglycemia characteristic of this model.
- Further studies are warranted to evaluate MK-0812 in alternative animal models or in conjunction with improved glycemic control for the prevention of diabetic complications.
