Dual CCR2/CCR5 antagonist treatment attenuates adipose inflammation, but not microvascular complications in ob/ob mice.
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.
Department of Neurology, University of Michigan, Ann Arbor, Michigan.
Phillipe D
PD
O'Brien
Department of Neurology, University of Michigan, Ann Arbor, Michigan.
Lucy M
LM
Hinder
Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
Sebastian D
SD
Parlee
Department of Neurology, University of Michigan, Ann Arbor, Michigan.
John M
JM
Hayes
Department of Neurology, University of Michigan, Ann Arbor, Michigan.
Carey
C
Backus
Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Hongyu
H
Zhang
Department of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, New Jersey.
Lijun
L
Ma
A. Alfred Taubman Medical Research Institute, University of Michigan, Ann Arbor, Michigan.
Stacey A
SA
Sakowski
Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
Frank C
FC
Brosius
Department of Neurology, University of Michigan, Ann Arbor, Michigan.
Eva L
0000-0002-9162-2694
EL
Feldman
D000273:Adipose Tissue / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000188:drug therapy; D003929:Diabetic Neuropathies / Q000188:drug therapy; D007249:Inflammation / Q000150:complications / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications / Q000188:drug therapy*; D015434:Panniculitis / Q000150:complications / Q000188:drug therapy; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors; D019713:Receptors, CCR5 / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C000592874:CCR5 protein, mouse; C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D019713:Receptors, CCR5
animal pharmacology; diabetes complications; diabetic nephropathy; diabetic neuropathy; drug mechanism; mouse model