Thrombospondin 1 mediates renal dysfunction in a mouse model of high-fat diet-induced obesity
Thrombospondin 1 mediates renal dysfunction in a mouse model of high-fat diet-induced obesity
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DOI：
10.1152/ajprenal.00209.2013
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发表时间：
2013-09-01
影响因子：
4.2
通讯作者：
Wang, Shuxia
中科院分区：
文献类型：
--
作者：
Cui, Wenpeng;Maimaitiyiming, Hasiyeti;Wang, Shuxia
肥胖在世界范围内普遍存在，是包括肾脏并发症在内的许多疾病的主要危险因素。血小板反应蛋白 1 (TSP1) 是一种多功能细胞外基质蛋白，在糖尿病肾病中发挥着重要作用。然而，TSP1 是否在肥胖相关肾脏疾病中发挥作用尚不清楚。在本研究中，通过饮食诱导的肥胖小鼠模型确定了 TSP1 在肥胖诱导的肾功能障碍中的作用。结果表明，肥胖小鼠肾脏中的 TSP1 显着上调。增加的 TSP1 位于肥胖野生型小鼠的肾小球系膜和肾小管系统中。肥胖野生型小鼠出现肾脏肥大和蛋白尿，这与肾脏巨噬细胞浸润增加、肾脏炎症加剧、转化生长因子 (TGF)-β 信号传导激活和肾脏纤维化有关。相比之下，肥胖的 TSP1 缺陷小鼠并没有出现这些肾脏损伤。此外，体外研究表明，瘦素治疗可刺激野生型小鼠肾小球系膜细胞中 TSP1、TGF-β1、纤连蛋白和 IV 型胶原的表达。这些瘦素刺激的作用在 TSP1 缺陷的系膜细胞中被消除。总而言之，这些数据表明 TSP1 是肥胖或高瘦素血症引起的肾功能障碍的重要介质。
Obesity is prevalent worldwide and is a major risk factor for many diseases including renal complications. Thrombospondin 1 (TSP1), a multifunctional extracellular matrix protein, plays an important role in diabetic kidney diseases. However, whether TSP1 plays a role in obesity-related kidney disease is unknown. In the present studies, the role of TSP1 in obesity-induced renal dysfunction was determined by using a diet-induced obese mouse model. The results demonstrated that TSP1 was significantly upregulated in the kidney from obese mice. The increased TSP1 was localized in the glomerular mesangium as well as in the tubular system from obese wild-type mice. Obese wild-type mice developed renal hypertrophy and albuminuria, which was associated with increased kidney macrophage infiltration, augmented kidney inflammation, and activated transforming growth factor (TGF)-beta signaling and renal fibrosis. In contrast, obese TSP1-deficient mice did not develop these kidney damages. Furthermore, in vitro studies demonstrated that leptin treatment stimulated the expression of TSP1, TGF-beta 1, fibronectin, and collagen type IV in mesangial cells isolated from wild-type mice. These leptin-stimulated effects were abolished in TSP1-deficient mesangial cells. Taken together, these data suggest that TSP1 is an important mediator for obesity-or hyperleptinemia-induced kidney dysfunction.