Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury.
BACKGROUND
Macrophage-mediated renal injury has been implicated in progressive forms of glomerulonephritis; however, a role for macrophages in type 2 diabetic nephropathy, the major cause of end-stage renal failure, has not been established. Therefore, we examined whether macrophages may promote the progression of type 2 diabetic nephropathy in db/db mice.


METHODS
The incidence of renal injury was examined in db/db mice with varying blood sugar and lipid levels at 8 months of age. The association of renal injury with the accumulation of kidney macrophages was analyzed in normal db/+ and diabetic db/db mice at 2, 4, 6, and 8 months of age.


RESULTS
In db/db mice, albuminuria and increased plasma creatinine correlated with elevated blood glucose and hemoglobin A1c (HbA1c) levels but not with obesity or hyperlipidemia. Progressive diabetic nephropathy in db/db mice was associated with increased kidney macrophages. Macrophage accumulation and macrophage activation in db/db mice correlated with hyperglycemia, HbA1c levels, albuminuria, elevated plasma creatinine, glomerular and tubular damage, renal fibrosis, and kidney expression of macrophage chemokines [monocyte chemoattractant protein-1 (MCP-1), osteopontin, migration inhibitory factor (MIF), monocyte-colony-stimulating factor (M-CSF)]. The accrual and activation of glomerular macrophages also correlated with increased glomerular IgG and C3 deposition, which was itself dependent on hyperglycemia.


CONCLUSIONS
Kidney macrophage accumulation is associated with the progression of type 2 diabetic nephropathy in db/db mice. Macrophage accumulation and activation in diabetic db/db kidneys is associated with prolonged hyperglycemia, glomerular immune complex deposition, and increased kidney chemokine production, and raises the possibility of specific therapies for targeting macrophage-mediated injury in diabetic nephropathy.
Chow
Fiona
F
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
Ozols
Elyce
E
Nikolic-Paterson
David J
DJ
Atkins
Robert C
RC
Tesch
Gregory H
GH
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000276:immunology / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000276:immunology* / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000453:epidemiology / Q000276:immunology* / Q000473:pathology*; D005260:Female; D005355:Fibrosis; D015870:Gene Expression / Q000276:immunology; D006943:Hyperglycemia / Q000276:immunology / Q000473:pathology; D015994:Incidence; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009765:Obesity; D053495:Osteopontin; D012795:Sialoglycoproteins / Q000235:genetics
D018932:Chemokine CCL2; D008263:Macrophage Migration-Inhibitory Factors; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D016173:Macrophage Colony-Stimulating Factor