Tubular Dickkopf-3 promotes the development of renal atrophy and fibrosis
Tubular Dickkopf-3 promotes the development of renal atrophy and fibrosis
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DOI：
10.1172/jci.insight.84916
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发表时间：
2016-01-21
期刊：
影响因子：
8
通讯作者：
Groene, Hermann-Josef
中科院分区：
文献类型：
--
作者：
Federico, Giuseppina;Meister, Michael;Groene, Hermann-Josef
肾小管萎缩和间质纤维化是病因不同的进行性慢性肾脏疾病（CKD）的共同标志，最终导致器官衰竭。尽管这些病理表现构成了一个重大的公共卫生问题，但诊断测试和治疗选择目前有限。dickkopf （DKK）家族成员DKK1和-2与Wnt信号传导抑制和器官纤维化有关。在这里，我们确定DKK3是应激诱导的、小管上皮衍生的、分泌的糖蛋白，介导肾纤维化。在两种肾纤维化小鼠模型中，遗传和抗体介导的DKK3缺失导致肾小管萎缩和间质基质积累减少。这是由应激小管上皮细胞中扩增的抗纤维化炎性T细胞反应和减少的典型Wnt/ β -连环蛋白信号促进的。此外，在人类中，尿DKK3水平与不同肾小球和小管间质疾病的小管萎缩和间质纤维化程度特异性相关。总之，我们的数据表明，DKK3是一种免疫抑制蛋白和促纤维化上皮蛋白，可能作为肾纤维化的潜在治疗靶点和诊断标志物。
Renal tubular atrophy and interstitial fibrosis are common hallmarks of etiologically different progressive chronic kidney diseases (CKD) that eventually result in organ failure. Even though these pathological manifestations constitute a major public health problem, diagnostic tests, as well as therapeutic options, are currently limited. Members of the dickkopf (DKK) family, DKK1 and -2, have been associated with inhibition of Wnt signaling and organ fibrosis. Here, we identify DKK3 as a stress-induced, tubular epithelia-derived, secreted glycoprotein that mediates kidney fibrosis. Genetic as well as antibody-mediated abrogation of DKK3 led to reduced tubular atrophy and decreased interstitial matrix accumulation in two mouse models of renal fibrosis. This was facilitated by an amplified, antifibrogenic, inflammatory T cell response and diminished canonical Wnt/beta-catenin signaling in stressed tubular epithelial cells. Moreover, in humans, urinary DKK3 levels specifically correlated with the extent of tubular atrophy and interstitial fibrosis in different glomerular and tubulointerstitial diseases. In summary, our data suggest that DKK3 constitutes an immunosuppressive and a profibrotic epithelial protein that might serve as a potential therapeutic target and diagnostic marker in renal fibrosis.