转录因子 ATF4 介导内质网应激相关足细胞损伤和裂隙隔膜缺陷,Kidney International

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转录因子 ATF4 介导内质网应激相关足细胞损伤和裂隙隔膜缺陷
Kidney International ( IF 14.8 ) Pub Date : 2022-12-29 , DOI: 10.1016/j.kint.2022.11.024
Vanessa Krausel ₁ , Lisanne Pund ₁ , Harald Nüsse ₂ , Hussein Bachir ₁ , Andrea Ricker ₂ , Jürgen Klingauf ₂ , Thomas Weide ₁ , Hermann Pavenstädt ₁ , Michael P Krahn ₁ , Daniela A Braun ₁

Affiliation

编码 KEOPS 复合体亚基的基因和其他四个基因的突变会导致加洛韦-莫瓦特综合征，这是一种严重的遗传性肾神经系统疾病。该复合物催化 tRNA 的重要转录后修饰，其功能丧失会引起内质网 (ER) 应激。在这里，我们利用花环肾细胞和培养的人足细胞，旨在阐明 KEOPS 相关肾小球疾病的分子致病机制，并测试 ER 应激相关信号传导的药理学抑制作为治疗原则。我们发现 ATF4（一种 ER 应激介导转录因子）或其果蝇直系同源物 Crc 在果蝇肾细胞和人类足细胞中表达上调。 Tcs3（果蝇 OSGEP 的直系同源物）的敲低会导致裂隙隔膜缺陷，重现人类肾脏表型。发现患者的cDNA带有突变，缺乏拯救能力。 Tcs3 缺陷肾细胞的遗传相互作用研究表明，Crc 不仅介导细胞损伤，而且令人惊讶地还介导裂隙隔膜缺陷，并且 Crc 激活的遗传或药理学抑制会减弱这两种表型。这些发现在人类足细胞中是保守的，其中 ATF4 抑制通过化学诱导的 ER 应激改善了 OSGEP 敲低的足细胞的活力，并且在 OSGEP 敲低后 ATF4 靶基因和促凋亡基因簇上调。因此，我们的数据表明 ATF4 介导的信号传导是 ER 应激、裂隙隔膜缺陷和足细胞损伤之间的分子联系，并且我们的数据表明 ATF4 信号传导的调节可能是某些足细胞疾病的潜在治疗靶点。

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The transcription factor ATF4 mediates endoplasmic reticulum stress-related podocyte injury and slit diaphragm defects

Mutations in and four other genes that encode subunits of the KEOPS complex cause Galloway-Mowat syndrome, a severe, inherited kidney-neurological disease. The complex catalyzes an essential posttranscriptional modification of tRNA and its loss of function induces endoplasmic reticulum (ER) stress. Here, using garland nephrocytes and cultured human podocytes, we aimed to elucidate the molecular pathogenic mechanisms of KEOPS-related glomerular disease and to test pharmacological inhibition of ER stress–related signaling as a therapeutic principle. We found that ATF4, an ER stress–mediating transcription factor, or its fly orthologue Crc, were upregulated in both fly nephrocytes and human podocytes. Knockdown of Tcs3, a fly orthologue of OSGEP, caused slit diaphragm defects, recapitulating the human kidney phenotype. cDNA with mutations found in patients lacked the capacity for rescue. Genetic interaction studies in Tcs3-deficient nephrocytes revealed that Crc mediates not only cell injury, but surprisingly also slit diaphragm defects, and that genetic or pharmacological inhibition of Crc activation attenuates both phenotypes. These findings are conserved in human podocytes where ATF4 inhibition improved the viability of podocytes with OSGEP knockdown, with chemically induced ER stress, and where ATF4 target genes and pro-apoptotic gene clusters are upregulated upon OSGEP knockdown. Thus, our data identify ATF4-mediated signaling as a molecular link among ER stress, slit diaphragm defects, and podocyte injury, and our data suggest that modulation of ATF4 signaling may be a potential therapeutic target for certain podocyte diseases.

更新日期：2022-12-29

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