Dickkopf-1 promotes hyperglycemia-induced accumulation of mesangial matrix and renal dysfunction.
Wnt/beta-catenin signaling mediates renal fibrosis in several model systems including diabetic nephropathy. Dickkopf-1 (DKK-1) is an endogenous inhibitor of Wnt/beta-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-beta1, and fibronectin in mesangial cells. Loss and gain of DKK1 function modulated HG-mediated c-Jun, TGF-beta1, and fibronectin expression. DKK1 mediated HG-induced phosphorylation of Ser45-beta-catenin and reduction of nuclear beta-catenin levels, but not phosphorylation of ERK kinase. Wnt3a protein and the beta-catenin (Delta45) mutation increased nuclear beta-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-beta1 and fibronectin and reduced both the glomerular volume and deposition of mesangial matrix in diabetic kidneys. Taken together, DKK1 mediates HG-induced destabilization of beta-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.
Lin
Chun-Liang
CL
Department of Nephrology, Chang Gung Memorial Hospital, Chiayi,Taiwan.
Wang
Jeng-Yi
JY
Ko
Jih-Yang
JY
Huang
Yu-Ting
YT
Kuo
Yu-Hsia
YH
Wang
Feng-Sheng
FS
D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology; D006943:Hyperglycemia / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013311:Streptozocin; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C531384:Dkk1 protein, rat; D005353:Fibronectins; D036341:Intercellular Signaling Peptides and Proteins; C546824:Kremen2 protein, rat; D011956:Receptors, Cell Surface; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D013311:Streptozocin; D048049:Extracellular Signal-Regulated MAP Kinases