Dickkopf-1 Promotes Hyperglycemia-Induced Accumulation of Mesangial Matrix and Renal Dysf unction
Dickkopf-1 Promotes Hyperglycemia-Induced Accumulation of Mesangial Matrix and Renal Dysf unction
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DOI：
10.1681/asn.2008101059
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发表时间：
2010-01-01
影响因子：
13.6
通讯作者：
Wang, Feng-Sheng
中科院分区：
文献类型：
--
作者：
Lin, Chun-Liang;Wang, Jeng-Yi;Wang, Feng-Sheng
Wnt/β-连环蛋白信号转导介导包括糖尿病肾病在内的几种模型系统中的肾纤维化。Dickkopf-1（DKK-1）是Wnt/β-连环蛋白信号传导的内源性抑制剂，但DKK-1是否调节糖尿病肾病尚不清楚。在此，我们研究了DKK-1是否参与高糖（HG）诱导的促纤维化因子表达和肾损伤。在体外，HG增加肾小球系膜细胞中DKK 1、受体Kremen-2、TGF-β 1和纤维连接蛋白的表达。DKK 1功能的丧失和获得调节HG介导的c-Jun、TGF-β 1和纤连蛋白表达。DKK 1介导HG诱导的Ser 45-beta-catenin磷酸化和细胞核beta-catenin水平降低，但不介导ERK激酶磷酸化。Wnt 3a蛋白和β-连环蛋白（Delta 45）突变增加了细胞核β-连环蛋白，但消除了HG诱导的DKK 1和纤连蛋白表达。外源性DKK 1反义寡核苷酸可抑制糖尿病大鼠血清DKK 1和尿蛋白排泄量的增加。敲低DKK 1可抑制糖尿病肾脏系膜TGF-β 1和纤维连接蛋白的表达，并减少肾小球体积和系膜基质沉积。总之，DKK 1介导HG诱导的β-连环蛋白的不稳定和系膜细胞中的基质积累。敲低DKK 1可预防糖尿病诱导的肾功能不全和微结构恶化，这表明抑制DKK 1可为糖尿病肾病提供治疗潜力。
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-beta 1, and fibronectin in mesangial cells. Loss and gain of DKK1 function modulated HG-mediated c-Jun, TGF-beta 1, 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 (Delta 45) 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-beta 1 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.