Biomedical Sciences, University of Edinburgh, Edinburgh, UK
III Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Life Sci Alliance. 2022 Aug 3;5(12):e202101281. doi: 10.26508/lsa.202101281.
Podocytes are specialized epithelial cells of the kidney glomerulus and are an essential part of the filtration barrier. Because of their position, they are exposed to constant biomechanical forces such as shear stress and hydrostatic pressure. These forces increase during disease, resulting in podocyte injury. It is likely podocytes have adaptative responses to help buffer against deleterious mechanical force and thus reduce injury. However, these responses remain largely unknown. Here, using the <i>Drosophila</i> model, we show the mechanosensor Cheerio (dFilamin) provides a key protective role in nephrocytes. We found expression of an activated mechanosensitive variant of Cheerio rescued filtration function and induced compensatory and hypertrophic growth in nephrocytes depleted of the nephrocyte diaphragm proteins Sns or Duf. Delineating the protective pathway downstream of Cheerio we found repression of the Hippo pathway induces nephrocyte hypertrophy, whereas Hippo activation reversed the Cheerio-mediated hypertrophy. Furthermore, we find Yorkie was activated upon expression of active Cheerio. Taken together, our data suggest that Cheerio acts via the Hippo pathway to induce hypertrophic growth, as a protective response in abnormal nephrocytes.
足细胞是肾脏肾小球的特化上皮细胞，是滤过屏障的重要组成部分。由于它们的位置，它们会受到持续的生物力学力的影响，如切应力和静水压力。在疾病期间，这些力会增加，导致足细胞损伤。足细胞可能具有适应性反应，以帮助缓冲有害的机械力，从而减少损伤。然而，这些反应在很大程度上仍然未知。在这里，我们使用<i>果蝇</i>模型，表明机械感受器 Cheerio（dFilamin）在肾细胞中提供了关键的保护作用。我们发现激活的 Cheerio 的机械敏感变体的表达挽救了滤过功能，并诱导了耗尽肾细胞膈蛋白 Sns 或 Duf 的肾细胞的代偿性和肥大性生长。阐明 Cheerio 下游的保护途径，我们发现抑制 Hippo 途径诱导肾细胞肥大，而 Hippo 激活则逆转了 Cheerio 介导的肥大。此外，我们发现表达活性 Cheerio 时 Yorkie 被激活。总之，我们的数据表明 Cheerio 通过 Hippo 途径激活，诱导异常肾细胞的肥大性生长，作为一种保护反应。
