KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progression.
KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progression.
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DOI：
10.1172/jci.insight.165002
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发表时间：
2023-04-10
期刊：
影响因子：
8
通讯作者：
Campbell, Kirk N.
中科院分区：
文献类型：
--
作者：
Meliambro, Kristin;Yang, Yanfeng;de Cos, Marina;Ballestas, Estefania Rodriguez;Malkin, Caroline;Haydak, Jonathan;Lee, John R.;Salem, Fadi;Mariani, Laura H.;Gordon, Ronald E.;Basgen, John M.;Wen, Huei Hsun;Fu, Jia;Azeloglu, Evren U.;He, John Cijiang;Wong, Jenny S.;Campbell, Kirk N.
尽管最近在鉴定足细胞损伤介质方面取得了进展，但足细胞损失的机制仍然知之甚少，并且缺乏细胞特异性治疗。我们之前报道过WWC1编码的肾和脑表达蛋白（KIBRA）通过激活Hippo信号通路在体外促进足细胞损伤。局灶节段性肾小球硬化患者的肾小球中 KIBRA 表达增加，体内 KIBRA 耗竭可预防急性足细胞损伤。在这里，我们测试了永生化人类足细胞和小鼠中转基因足细胞特异性 WWC1 表达的后果，并探讨了肾小球 WWC1 表达与肾小球疾病进展之间的关联。我们发现永生化人足细胞中 KIBRA 过度表达促进 Yes 相关蛋白 (YAP) 的细胞质定位，诱导肌动蛋白细胞骨架重组，并改变粘着斑表达和形态。 WWC1 转基因（KIBRA 过表达）小鼠更容易受到急性和慢性肾小球损伤，有体内 YAP 抑制的证据。具有临床相关性的是，肾小球WWC1表达与原发性肾小球疾病患者的肾存活率呈负相关。这些发现强调了 KIBRA/YAP 信号传导对足细胞结构完整性调节的重要性，并将 KIBRA 介导的损伤确定为肾小球疾病足细胞特异性治疗的潜在靶标。
Despite recent progress in the identification of mediators of podocyte injury, mechanisms underlying podocyte loss remain poorly understood, and cell-specific therapy is lacking. We previously reported that kidney and brain expressed protein (KIBRA), encoded by WWC1, promotes podocyte injury in vitro through activation of the Hippo signaling pathway. KIBRA expression is increased in the glomeruli of patients with focal segmental glomerulosclerosis, and KIBRA depletion in vivo is protective against acute podocyte injury. Here, we tested the consequences of transgenic podocyte-specific WWC1 expression in immortalized human podocytes and in mice, and we explored the association between glomerular WWC1 expression and glomerular disease progression. We found that KIBRA overexpression in immortalized human podocytes promoted cytoplasmic localization of Yes-associated protein (YAP), induced actin cytoskeletal reorganization, and altered focal adhesion expression and morphology. WWC1-transgenic (KIBRA-overexpressing) mice were more susceptible to acute and chronic glomerular injury, with evidence of YAP inhibition in vivo. Of clinical relevance, glomerular WWC1 expression negatively correlated with renal survival among patients with primary glomerular diseases. These findings highlight the importance of KIBRA/YAP signaling to the regulation of podocyte structural integrity and identify KIBRA-mediated injury as a potential target for podocyte-specific therapy in glomerular disease.
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影响因子：
4.8
作者：
Meliambro, Kristin;Wong, Jenny S.;Campbell, Kirk N.
通讯作者：
Campbell, Kirk N.
影响因子：
9.8
作者：
Rosse C;Formstecher E;Boeckeler K;Zhao Y;Kremerskothen J;White MD;Camonis JH;Parker PJ
通讯作者：
Parker PJ
影响因子：
11.8
作者：
Genevet A;Wehr MC;Brain R;Thompson BJ;Tapon N
通讯作者：
Tapon N
影响因子：
8.8
作者：
Liu X;Li H;Rajurkar M;Li Q;Cotton JL;Ou J;Zhu LJ;Goel HL;Mercurio AM;Park JS;Davis RJ;Mao J
通讯作者：
Mao J
影响因子：
19.6
作者：
Reiser, Jochen;Gupta, Vineet;Kistler, Andreas D.
通讯作者：
Kistler, Andreas D.