Thrombospondin 1 Deficiency Ameliorates the Development of Adriamycin-Induced Proteinuric Kidney Disease.
Thrombospondin 1 Deficiency Ameliorates the Development of Adriamycin-Induced Proteinuric Kidney Disease.
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DOI：
10.1371/journal.pone.0156144
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Maimaitiyiming H;Zhou Q;Wang S
越来越多的证据表明，血小板反应蛋白1（TSP1）是糖尿病肾病的重要参与者。然而，TSP1在足细胞损伤和非糖尿病性蛋白尿肾病发展中的作用在很大程度上是未知的。在目前的研究中，通过使用一个完善的足细胞损伤模型（阿霉素诱导的肾病小鼠模型），我们研究了TSP 1的蛋白尿肾病的发展的贡献。我们发现，在蛋白尿发生之前，注射阿霉素的小鼠的肾小球中，特别是足细胞中，TSP 1上调。ADR处理还刺激体外培养的人足细胞中TSP1的表达。此外，增加TSP 1介导的ADR诱导足细胞凋亡和肌动蛋白细胞骨架解体。TSP1的这种作用是通过CD36依赖性机制，并参与p38MAPK通路的刺激。重要的是，体内数据表明，TSP1缺陷保护小鼠免受ADR诱导的足细胞损失和足突消失。ADR诱导的蛋白尿、肾小球硬化、肾巨噬细胞浸润和炎症在TSP1缺陷小鼠中也减弱。总之，这些研究提供了新的证据，表明TSP1通过刺激足细胞损伤和肾脏炎症的进展而促进非糖尿病蛋白尿肾病的发展。
Accumulating evidence suggests that thrombospondin 1 (TSP1) is an important player in diabetic nephropathy. However, the role of TSP1 in podocyte injury and the development of non-diabetic proteinuric kidney disease is largely unknown. In the current study, by using a well-established podocyte injury model (adriamycin-induced nephropathy mouse model), we examined the contribution of TSP1 to the development of proteinuric kidney disease. We found that TSP1 was up-regulated in the glomeruli, notably in podocytes, in adriamycin injected mice before the onset of proteinuria. ADR treatment also stimulated TSP1 expression in cultured human podocytes in vitro. Moreover, increased TSP1 mediated ADR-induced podocyte apoptosis and actin cytoskeleton disorganization. This TSP1’s effect was through a CD36-dependent mechanism and involved in the stimulation of p38MAPK pathway. Importantly, in vivo data demonstrated that TSP1 deficiency protected mice from ADR induced podocyte loss and foot process effacement. ADR induced proteinuria, glomerulosclerosis, renal macrophage infiltration and inflammation was also attenuated in TSP1 deficient mice. Taken together, these studies provide new evidence that TSP1 contributes to the development of non-diabetic proteinuric kidney disease by stimulating podocyte injury and the progression of renal inflammation.