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Published online before print September 20, 2007
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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070079

Accepted for publication August 14, 2007.

Article

Decorin Deficiency Enhances Progressive Nephropathy in Diabetic Mice

Kevin Jon Williams*, Gang Qiu{dagger}, Hitomi Katoaka Usui{dagger}, Stephen R. Dunn{dagger}, Peter McCue{ddagger}, Erwin Bottinger{sect}, Renato V. Iozzo{ddagger}, and Kumar Sharma{dagger}@

From the Division of Endocrinology, Diabetes and Metabolic Diseases,* Center for Novel Therapies for Kidney Disease,{dagger} Division of Nephrology, Dorrance Hamilton Research Laboratories, Department of Medicine, Department of Pathology, Anatomy and Cell Biology,{ddagger} and the Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and the Division of Nephrology,{sect} Department of Medicine, Mount Sinai School of Medicine, New York, New York

@ To whom correspondence should be addressed. E-mail: KumarSharma{at}ucsd.edu.


  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.




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L. Schaefer and R. V. Iozzo
Biological Functions of the Small Leucine-rich Proteoglycans: From Genetics to Signal Transduction
J. Biol. Chem., August 1, 2008; 283(31): 21305 - 21309.
[Abstract] [Full Text] [PDF]


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Copyright © 2007 by the American Society for Investigative Pathology.