Tubule-specific ablation of endogenous β-catenin aggravates acute kidney injury in mice.
Tubule-specific ablation of endogenous β-catenin aggravates acute kidney injury in mice.
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内源性β-连环蛋白的肾小管特异性消融会加重小鼠急性肾损伤
DOI：
10.1038/ki.2012.173
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发表时间：
2012-09
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
--
作者：
β-连环蛋白是一种独特的细胞内蛋白，作为细胞-细胞粘附复合物的组成部分和介导经典Wnt信号传导的主要信号传导蛋白发挥作用。关于其在正常生理状态下或急性肾损伤（阿基）后在成人肾脏中的功能知之甚少。为了研究这一点，我们产生了条件性敲除小鼠，其中β-catenin基因在肾小管中被特异性破坏（Ksp-β-cat−/−）。这些小鼠表型正常，肾脏形态和功能无明显缺陷。在β-连环蛋白不存在的情况下，γ-连环蛋白在功能上取代了它与E-钙粘蛋白的结合，从而维持了肾脏中上皮粘附连接的完整性。在缺血再灌注或叶酸诱导的阿基中，肾小管β-catenin的丢失显著加重了肾脏病变。与对照组相比，Ksp-β-cat−/−小鼠的死亡率更高，血清肌酐升高，形态学损伤更严重。结论：基因敲除小鼠肾脏细胞凋亡明显增加，p53和Bax表达增加，磷酸化Akt和Survivin表达减少。在体外，Wnt 1激活β-catenin或稳定β-catenin可保护肾小管上皮细胞免于凋亡，激活Akt，诱导survivin，并抑制p53和Bax表达。因此，内源性β-连环蛋白通过多种机制促进细胞存活，对于阿基后的肾小管保护至关重要。
β-catenin is a unique intracellular protein functioning as an integral component of the cell-cell adherens complex and a principal signaling protein mediating canonical Wnt signaling. Little is known about its function in adult kidneys in the normal physiologic state or after acute kidney injury (AKI). To study this, we generated conditional knockout mice in which the β-catenin gene was specifically disrupted in renal tubules (Ksp-β-cat−/−). These mice were phenotypically normal with no appreciable defects in kidney morphology and function. In the absence of β-catenin, γ-catenin functionally substituted it for E-cadherin binding, thereby sustaining the integrity of epithelial adherens junctions in the kidneys. In AKI induced by ischemia reperfusion or folic acid, the loss of tubular β-catenin substantially aggravated renal lesions. Compared with controls, Ksp-β-cat−/− mice displayed higher mortality, elevated serum creatinine and more severe morphologic injury. Consistently, apoptosis was more prevalent in kidneys of the knockout mice, which was accompanied by increased expression of p53 and Bax, and decreased phosphorylated Akt and survivin. In vitro, activation of β-catenin by Wnt1 or stabilization of β-catenin protected tubular epithelial cells from apoptosis, activated Akt, induced survivin, and repressed p53 and Bax expression. Hence, endogenous β-catenin is pivotal for renal tubular protection after AKI by promoting cell survival through multiple mechanisms.
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DOI：
10.1042/bj20100814
发表时间：
2010-09-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Altieri DC
通讯作者：
Altieri DC
tPA 保护肾间质成纤维细胞和肌成纤维细胞免于凋亡
影响因子：
13.6
作者：
Hu, Kebin;Lin, Ling;Liu, Youhua
通讯作者：
Liu, Youhua
影响因子：
19.6
作者：
Linkermann, Andreas;Braesen, Jan H.;Krautwald, Stefan
通讯作者：
Krautwald, Stefan
影响因子：
19.6
作者：
Li, Yingjian;Wen, Xiaoyan;Liu, Youhua
通讯作者：
Liu, Youhua
影响因子：
13.6
作者：
Dai, CS;Yang, JW;Liu, YH
通讯作者：
Liu, YH