Loss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease.
Loss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease.
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足细胞中 CLDN5 的缺失会导致 WIF1 失调，从而激活 WNT 信号传导并导致肾脏疾病
DOI：
10.1038/s41467-022-29277-6
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发表时间：
2022-03-24
影响因子：
16.6
通讯作者：
Gong Y
中科院分区：
文献类型：
--
作者：
Sun H;Li H;Yan J;Wang X;Xu M;Wang M;Fan B;Liu J;Lin N;Wang X;Li L;Zhao S;Gong Y
尽管成熟的足细胞缺乏紧密连接，但紧密连接蛋白Claudin-5(CLDN5)在正常情况下主要表达在足细胞的质膜上。利用足细胞特异的Cldn5基因敲除小鼠，我们发现CLDN5是足细胞功能的关键调节因子，并揭示了Cldn5缺失会加剧糖尿病肾病小鼠模型的足细胞损伤和蛋白尿。从机制上讲，CLDN5的缺失降低了ZO1的表达，诱导了ZONAB的核移位，进而导致WNT抑制因子-1(WIF1)的转录下调，从而导致WNT信号通路的激活。足细胞来源的WIF1也在肾小管上皮细胞中发挥旁分泌作用，这一发现证明，足细胞特异性缺失Cldn5或Wif1的动物在单侧输尿管梗阻后肾脏纤维化比斜位对照组更严重。全身注射WIF1可抑制糖尿病肾病和输尿管梗阻所致肾纤维化的进展。这些发现证实了足细胞CLDN5在限制肾脏WNT信号转导中的作用。Claudin-5是一种紧密连接的完整膜蛋白，但在缺乏紧密连接的成熟足细胞中也有表达。在这里，作者报道足细胞claudin-5通过调节WIF1的表达来调节WNT信号的活性，它的下调有助于小鼠肾脏疾病的进展。
Although mature podocytes lack tight junctions, tight junction integral membrane protein claudin-5 (CLDN5) is predominantly expressed on plasma membranes of podocytes under normal conditions. Using podocyte-specific Cldn5 knockout mice, we identify CLDN5 as a crucial regulator of podocyte function and reveal that Cldn5 deletion exacerbates podocyte injury and proteinuria in a diabetic nephropathy mouse model. Mechanistically, CLDN5 deletion reduces ZO1 expression and induces nuclear translocation of ZONAB, followed by transcriptional downregulation of WNT inhibitory factor-1 (WIF1) expression, which leads to activation of WNT signaling pathway. Podocyte-derived WIF1 also plays paracrine roles in tubular epithelial cells, as evidenced by the finding that animals with podocyte-specific deletion of Cldn5 or Wif1 have worse kidney fibrosis after unilateral ureteral obstruction than littermate controls. Systemic delivery of WIF1 suppresses the progression of diabetic nephropathy and ureteral obstruction-induced renal fibrosis. These findings establish a function for podocyte CLDN5 in restricting WNT signaling in kidney. Claudin-5 is a tight junction integral membrane protein, but it is also expressed in mature podocytes which lack tight junctions. Here the authors report that podocyte claudin-5 regulates WNT signaling activity by modulating WIF1 expression, and its downregulation contributes to kidney disease progression in mice.
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影响因子：
11.4
作者：
Balda, MS;Matter, K
通讯作者：
Matter, K
影响因子：
7.8
作者：
Nitta, T;Hata, M;Tsukita, S
通讯作者：
Tsukita, S
影响因子：
19.6
作者：
Done, S. C.;Takemoto, M.;Tryggvason, K.
通讯作者：
Tryggvason, K.
DOI：
10.1073/pnas.0504166102
发表时间：
2005-07-12
影响因子：
11.1
作者：
Lehtonen, S;Ryan, JJ;Farquhar, MG
通讯作者：
Farquhar, MG
DOI：
10.1038/mtm.2014.14
发表时间：
2014
期刊：
Molecular therapy. Methods & clinical development
影响因子：
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作者：
通讯作者：
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