Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis.
Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis.
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肌成纤维细胞在纤维化中的功能作用尚不清楚。使用一种新的遗传小鼠模型来跟踪和分离肌成纤维细胞，我们进行了基因表达谱分析，然后进行了生物学验证，以确定人类附睾蛋白4 （HE4，也称为WAP 4-二硫核结构域-2或Wfdc2）是纤维化相关肌成纤维细胞中上调最多的基因。HE4基因编码一种假定的丝氨酸蛋白酶抑制剂，该抑制剂在人和小鼠的纤维化肾脏中表达上调，在肾纤维化患者的血清中表达升高。HE4抑制多种蛋白酶的活性，包括丝氨酸蛋白酶和基质金属蛋白酶，并特异性地抑制它们降解I型胶原的能力。特别是，我们确定了两种新的丝氨酸蛋白酶，Prss35和Prss23，作为HE4靶点，在肾纤维化中具有功能相关性。在三种不同的肾脏疾病小鼠模型中，给予HE4中和抗体加速I型胶原降解并抑制纤维化。总的来说，这些研究表明HE4是肾纤维化的潜在生物标志物和新的治疗靶点。
The functional contribution of myofibroblasts in fibrosis is not well understood. Using a novel genetic mouse model to track and isolate myofibroblasts, we performed gene expression profiling followed by biological validation to identify human epididymis protein 4 (HE4, also known as WAP 4-disulfide core domain-2 or Wfdc2) as the most up-regulated gene in fibrosis-associated myofibroblasts. The HE4 gene encodes for a putative serine protease inhibitor that is upregulated in human and mouse fibrotic kidneys, and elevated in the serum of patients with kidney fibrosis. HE4 suppresses the activity of multiple proteases, including serine proteases and matrix metalloproteinases, and specifically inhibits their capacity to degrade type I collagen. In particular, we identified two novel serine proteases, Prss35 and Prss23, as HE4 targets with functional relevance in kidney fibrosis. Administration of HE4 neutralizing antibodies accelerated collagen I degradation and inhibited fibrosis in three different mouse models of renal disease. Collectively, these studies suggest that HE4 is a potential biomarker of renal fibrosis and a novel therapeutic target.
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