Loss of PTEN promotes podocyte cytoskeletal rearrangement, aggravating diabetic nephropathy.
Loss of PTEN promotes podocyte cytoskeletal rearrangement, aggravating diabetic nephropathy.
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DOI：
10.1002/path.4508
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发表时间：
2015-05
影响因子：
7.3
通讯作者：
Xu, Jing
中科院分区：
文献类型：
--
作者：
Lin, Jamie S.;Shi, Yuanyuan;Peng, Hui;Shen, Xiaojie;Thomas, Sandhya;Wang, Yanlin;Truong, Luan D.;Dryer, Stuart E.;Hu, Zhaoyong;Xu, Jing
在糖尿病肾病（DN）中，足细胞骨架重排发生，随后足细胞消失和蛋白尿的发展。PTEN（phosphatase and tensin homolog，磷酸酶和张力蛋白同源物）是一种广泛表达的磷酸酶，在细胞增殖、细胞骨架重排和运动中起关键作用。据报道，在糖尿病小鼠模型中，系膜细胞中的PTEN表达降低，导致系膜基质的扩张，但足细胞中的PTEN如何影响DN的发展尚不清楚。我们观察到糖尿病db/db小鼠和DN患者足细胞中PTEN表达下调。在培养的足细胞中，PTEN抑制引起肌动蛋白细胞骨架重排，这种反应与小GTP酶Rac 1/Cdc 42和RhoA的不平衡激活有关。在用PTEN抑制剂处理的小鼠中，足细胞中发生肌动蛋白细胞骨架重排，并伴随白蛋白排泄增加。我们还创建了在足细胞中选择性缺失PTEN的小鼠。这些小鼠表现出白蛋白排泄增加和中度足突消失。当用高脂肪饮食攻击小鼠时，与喂食高脂肪饮食的对照小鼠或喂食正常饮食的PTEN缺失小鼠相比，足细胞特异性敲除PTEN导致蛋白尿和肾小球球蛋白显著增加。这些结果表明，PTEN参与足细胞中细胞骨架重排的调节，并且PTEN的缺失易于发生蛋白尿和DN。
In diabetic nephropathy (DN), podocyte cytoskeletal rearrangement occurs followed by podocyte effacement and the development of proteinuria. PTEN (phosphatase and tensin homolog) is a ubiquitously expressed phosphatase that plays a critical role in cell proliferation, cytoskeletal rearrangement and motility. In mouse models of diabetes mellitus, PTEN expression is reportedly decreased in mesangial cells contributing to expansion of the mesangial matrix, but how PTEN in the podocyte influences the development of DN is unknown. We observed that PTEN expression is down-regulated in the podocytes of diabetic db/db mice and patients with DN. In cultured podocytes PTEN inhibition caused actin cytoskeletal rearrangement and this response was associated with unbalanced activation of small GTPases Rac1/Cdc42 and RhoA. In mice treated with PTEN inhibitor, actin cytoskeletal rearrangement occurred in podocytes and was accompanied by increased albumin excretion. We also created mice with an inducible deletion of PTEN selectively in podocytes. These mice exhibited increased albumin excretion and moderate foot process effacement. When the mice were challenged with a high fat diet, podocyte-specific knockout of PTEN resulted in substantially increased proteinuria and glomeruloclerosis compared to control mice fed a high fat diet or mice with PTEN deletion fed a normal diet. These results indicate that PTEN is involved in the regulation of cytoskeletal rearrangement in podocytes and that loss of PTEN predisposes to the development of proteinuria and DN.
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影响因子：
18.2
作者：
Greka A;Mundel P
通讯作者：
Mundel P
影响因子：
21.3
作者：
Li, Z;Dong, XM;Wu, DQ
通讯作者：
Wu, DQ
影响因子：
19.6
作者：
Ma, LJ;Fogo, AB
通讯作者：
Fogo, AB
影响因子：
7.7
作者：
Hu Z;Wang H;Lee IH;Modi S;Wang X;Du J;Mitch WE
通讯作者：
Mitch WE
影响因子：
56.9
作者：
Han, JW;Luby-Phelps, K;Broek, D
通讯作者：
Broek, D