TY - JOUR
T1 - Decorin deficiency enhances progressive nephropathy in diabetic mice
AU - Williams, Kevin Jon
AU - Qiu, Gang
AU - Usui, Hitomi Katoaka
AU - Dunn, Stephen R.
AU - McCue, Peter
AU - Bottinger, Erwin
AU - Iozzo, Renato V.
AU - Sharma, Kumar
N1 - Funding Information:
Portions of this manuscript were presented in abstract form at the ASN meeting 2004. Funding for this study was provided by grant U01 DK60995 (E.B., K.J.W., and K.S.). Additional funding for portions of this work was provided by National Institutes of Health grants DK053867 (K.S.), HL56984 (K.J.W.), and CA 39481 (R.V.I.) .
PY - 2007/11
Y1 - 2007/11
N2 - Decorin, a proteoglycan that inhibits active transforming growth factor-β, 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-β, 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.
AB - Decorin, a proteoglycan that inhibits active transforming growth factor-β, 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-β, 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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U2 - 10.2353/ajpath.2007.070079
DO - 10.2353/ajpath.2007.070079
M3 - Article
C2 - 17884968
AN - SCOPUS:36348995969
SN - 0002-9440
VL - 171
SP - 1441
EP - 1450
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -