Decorin deficiency enhances progressive nephropathy in diabetic mice

Am J Pathol. 2007 Nov;171(5):1441-50. doi: 10.2353/ajpath.2007.070079. Epub 2007 Sep 20.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Collagen Type I / metabolism
  • Decorin
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology*
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology*
  • Diabetes Mellitus, Type 1 / physiopathology
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology*
  • Diabetic Nephropathies / physiopathology
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / physiology*
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NADPH Oxidase 4
  • NADPH Oxidases / metabolism
  • Proteoglycans / genetics
  • Proteoglycans / physiology*
  • Streptozocin
  • Transforming Growth Factor beta / metabolism

Substances

  • Collagen Type I
  • Dcn protein, mouse
  • Decorin
  • Extracellular Matrix Proteins
  • Proteoglycans
  • Transforming Growth Factor beta
  • Streptozocin
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse