Role of platelet-derived growth factor (PDGF)-DD in renal fibrosis

约5-10%的一般人群表现出中度至高度肾功能受损（慢性肾脏疾病：CKD）。CKD的普遍组织学相关性是肾纤维化，这是一种以肾间充质细胞（例如成纤维细胞和系膜细胞）的活化和增殖为特征的过程。我们可以证明，血小板衍生生长因子（PDGF）-DD，一个高亲和力的PDGF受体β链的配体，是一个重要的因素驱动肾小球系膜细胞在体外和体内增殖。迄今为止，关于PDGF-DD在肾脏疾病中的其他作用（特别是促纤维化作用）的额外信息很少。在其他器官中获得的数据表明，PDGF系统本身是影响间充质细胞（即驱动肾纤维化的主要细胞）增殖和活化的主要因素之一。在此，我们假设PDGF-DD通过对肾小球系膜细胞和肾小管间质成纤维细胞的作用在肾纤维化中起重要作用。为了解决这一假设，我们将使用新开发的PDGF-DD敲除小鼠和不同的肾纤维化和系膜应激的动物模型。我们将通过使用原代系膜细胞和肾成纤维细胞的体外实验来证实这些结果。这些数据可能导致PDGF-DD被鉴定为肾纤维化的新治疗靶点。

About 5-10% of the general population exhibit moderately to highly impaired renal function (chronic kidney disease: CKD). The universal histological correlate of CKD is renal fibrosis, a process characterized by activation and proliferation of renal mesenchymal cells, e.g. fibroblasts and mesangial cells. We could demonstrate that platelet-derived growth factor (PDGF)–DD, a high-affinity ligand of the PDGF receptor β-chain, is an important factor driving proliferation of glomerular mesangial cells in vitro and in vivo. To date, there is very little additional information on other, in particular pro-fibrotic, roles of PDGF-DD in renal diseases. Data obtained in other organs show that the PDGF system per se is one of the major factors affecting proliferation and activation of mesenchymal cells, i.e. the principal cells driving renal fibrosis. Here, we hypothesize that PDGF-DD plays an important role in renal fibrosis via actions on glomerular mesangial cells and tubulointerstitial fibroblasts. To address this hypothesis, we will use newly developed PDGF-DD knock-out mice and different animal models of renal fibrosis and mesangial stress. We will corroborate these results by in vitro experiments using primary mesangial cells and renal fibroblasts. Potentially, these data could lead to the identification of PDGF-DD as a novel treatment target in renal fibrosis.