Drosophila Filamin exhibits a mechano-protective role during nephrocyte injury via induction of hypertrophic growth
Drosophila Filamin exhibits a mechano-protective role during nephrocyte injury via induction of hypertrophic growth
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果蝇细丝蛋白通过诱导肥大生长在肾细胞损伤过程中表现出机械保护作用
DOI：
10.1101/2021.08.20.457058
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发表时间：
--
期刊：
影响因子：
--
通讯作者：
Denholm
中科院分区：
文献类型：
--
作者：
Koehler;Denholm
足细胞是肾小球高度特化的上皮细胞，是滤过屏障的重要组成部分。由于它们在肾脏中的位置和功能，它们暴露于恒定的生物力学力，如剪切应力和静水压力。这些力量在疾病期间增加，导致足细胞损伤和丢失。生物力学力被感知和转导以引发适应性和保护性反应的机制在很大程度上仍然未知。在这里，我们使用果蝇肾细胞模型表明，机械传感器Cheerio （dFilamin）是这种“机械保护”机制的核心。我们在受损肾细胞中发现了一种激活的Cheerio诱导的肥大和恢复滤过功能的机械敏感变体的表达。对人丝蛋白B的进一步分析证实了这种机械保护作用。我们描绘了Cheerio下游的机械保护途径，发现TOR和Yorkie的激活诱导肾细胞肥大，而它们的抑制逆转了Cheerio介导的肥大。尽管Cheerio/Filamin B通路在面对损伤时介导机械保护作用，但我们发现过度活性导致病理表型，表明活性水平必须严格控制。综上所述，我们的数据表明Cheerio通过TOR和YAP途径诱导肥厚性生长，作为肾细胞损伤的机械保护反应。
Podocytes are highly specialized epithelial cells of the kidney glomerulus and are an essential part of the filtration barrier. Due to their position and function in the kidney, they are exposed to constant biomechanical forces such as shear stress and hydrostatic pressure. These forces increase during disease, resulting in podocyte injury and loss. The mechanism by which biomechanical forces are sensed and transduced to elicit an adaptive and protective response remains largely unknown. Here we show, using theDrosophilanephrocyte model, that the mechanosensor Cheerio (dFilamin) is central to this ‘mechano-protective’ mechanism. We found expression of an activated mechanosensitive variant of Cheerio induced hypertrophy and rescued filtration function in injured nephrocytes. Additional analysis with human Filamin B confirmed this mechano-protective role. We delineated the mechano-protective pathway downstream of Cheerio and found activation of TOR and Yorkie induce nephrocyte hypertrophy, whereas their repression reversed the Cheerio-mediated hypertrophy. Although Cheerio/Filamin B pathway mediates a mechano-protective role in the face of injury, we found excessive activity resulted in a pathological phenotype, indicating activity levels must be tightly controlled. Taken together, our data suggest that Cheerio acts via the TOR and YAP pathway to induce hypertrophic growth, as a mechano-protective response to nephrocyte injury.
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留下的压力屏障：随机足细胞消融引发继发性损伤。
DOI：
10.1152/ajprenal.00109.2021
发表时间：
2021
期刊：
American journal of physiology. Renal physiology
影响因子：
--
作者：
Sybille Koehler;Markus M. Rinschen
通讯作者：
Markus M. Rinschen
影响因子：
13.6
作者：
Schwartzman, Monica;Reginensi, Antoine;Campbell, Kirk N.
通讯作者：
Campbell, Kirk N.
影响因子：
4
作者：
Kuelshammer, Eva;Uhlirova, Mirka
通讯作者：
Uhlirova, Mirka
影响因子：
13.6
作者：
Wiggins, JE;Goyal, M;Wiggins, RC
通讯作者：
Wiggins, RC
影响因子：
20.8
作者：
Butt, Linus;Unnersjoe-Jess, David;Benzing, Thomas
通讯作者：
Benzing, Thomas