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.
OBJECTIVE
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.


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
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.
Chow
F Y
FY
Department of Nephrology, Monash Medical Centre, Clayton, VIC, 3168, Australia.
Nikolic-Paterson
D J
DJ
Ma
F Y
FY
Ozols
E
E
Rollins
B J
BJ
Tesch
G H
GH
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D016133:Polymerase Chain Reaction
D001786:Blood Glucose; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2