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Dickkopf-1 Promotes Hyperglycemia–Induced Accumulation of Mesangial Matrix and Renal Dysfunction

Chun-Liang Lin^*,,, Jeng-Yi Wang, Jih-Yang Ko^||,¶, Yu-Ting Huang^*, Yu-Hsia Kuo^* and Feng-Sheng Wang^||,**

Departments of *Nephrology and
Colorectal Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan;
Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taipei, Taiwan;
School of Traditional Chinese Medicine and
^||Graduate Institute of Clinical Medical Science, Chang Gung University College of Medicine, Taipei, Taiwan; and
Departments of ^¶Orthopedic Surgery and
**Medical Research, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan

Correspondence: Dr. Feng-Sheng Wang, Department of Medical Research, Kaohisung Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan. Phone: +886-7-731-7123, ext. 8876; Fax: +886-7-7338456; E-mail: wangfs{at}ms33.hinet.net, linchunliang{at}adm.cgmh.org.tw

Received for publication October 9, 2008. Accepted for publication September 9, 2009.

Wnt/β-catenin signaling mediates renal fibrosis in several model systems including diabetic nephropathy. Dickkopf-1 (DKK-1) is an endogenous inhibitor of Wnt/β-catenin signaling, but whether DKK-1 modulates diabetic nephropathy is unknown. Here, we studied whether DKK-1 participates in high glucose (HG)-induced expression of profibrotic factors and renal damage. In vitro, HG increased expression of DKK1, receptor Kremen-2, TGF-β1, and fibronectin in mesangial cells. Loss and gain of DKK1 function modulated HG-mediated c-Jun, TGF-β1, and fibronectin expression. DKK1 mediated HG-induced phosphorylation of Ser45-β-catenin and reduction of nuclear β-catenin levels, but not phosphorylation of ERK kinase. Wnt3a protein and the β-catenin (45) mutation increased nuclear β-catenin but abrogated HG-induced DKK1 and fibronectin expression. Exogenous DKK1 antisense oligonucleotide attenuated the increase in both serum DKK1 and urinary protein excretion in streptozotocin-induced diabetic rats. Knocking down DKK1 inhibited mesangial expression of TGF-β1 and fibronectin and reduced both the glomerular volume and deposition of mesangial matrix in diabetic kidneys. Taken together, DKK1 mediates HG-induced destabilization of β-catenin and matrix accumulation in mesangial cells. Knocking down DKK1 prevents diabetes-induced renal dysfunction and microstructure deterioration, suggesting that inhibition of DKK1offers therapeutic potential for diabetic nephropathy.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673