Decorin deficiency enhances progressive nephropathy in diabetic mice.
Decorin, a proteoglycan that inhibits active transforming growth factor-beta, is increased in diabetic nephropathy; however, its functional significance is unclear. In this study, we used low-dose streptozotocin to induce type 1 diabetes in wild-type (C57BL/6J Dcn(+/+)), Dcn(-/-), and Dcn(+/-) mice and studied the mice for up to 1 year of diabetes. Decorin gene dose had no effect on severity of diabetes; however, the Dcn(-/-) diabetic mice died significantly earlier than nondiabetic controls (57 versus 7.3% mortality). In contrast to wild-type diabetic mice, which failed to develop significant nephropathy, the Dcn(-/-) diabetic mice developed a significant increase in albuminuria and plasma creatinine and a concurrent decrease in circulating adiponectin levels. Interestingly, adiponectin levels at 6 months of diabetes were predictive of mortality in diabetic mice. Dcn(-/-) diabetic mice exhibited advanced glomerular lesions, including diffuse mesangial matrix accumulation and fibrin cap formation. By immunohistochemistry, Dcn(-/-) diabetic mice exhibited significant increases in glomerular transforming growth factor-beta, type I collagen, macrophage infiltration, and Nox4. We conclude that decorin is a natural protective factor against diabetic nephropathy and that the Dcn(-/-) diabetic mouse is a useful new model of progressive diabetic nephropathy.
Williams
Kevin Jon
KJ
Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Qiu
Gang
G
Usui
Hitomi Katoaka
HK
Dunn
Stephen R
SR
McCue
Peter
P
Bottinger
Erwin
E
Iozzo
Renato V
RV
Sharma
Kumar
K
D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D058575:Decorin; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000502:physiology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D011509:Proteoglycans / Q000235:genetics / Q000502:physiology*; D013311:Streptozocin; D016212:Transforming Growth Factor beta / Q000378:metabolism
D024042:Collagen Type I; C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; D013311:Streptozocin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse