Zhao Yunpo, Duan Jianli, Han Iden D, van de Leemput Joyce, Ray Patricio E, Han Zhe
Center for Precision Disease Modeling, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
J Am Soc Nephrol. 2025 Mar 1;36(3):393-405. doi: 10.1681/ASN.0000000529. Epub 2024 Oct 17.
Piezo channels, known for detecting mechanical pressure, were found to be expressed at the lacuna channel membranes of nephrocytes. Piezo loss of function caused nephrocyte dysfunction, including disrupted slit diaphragm structure and altered lacuna channel morphology. Piezo deficiency led to internalized slit diaphragm proteins, reduced autophagy, increased endoplasmic reticulum stress, and impaired calcium homeostasis.
The gene encodes a highly conserved cell membrane protein responsible for sensing pressure. The glomerular kidney and the slit diaphragm filtration structure depend on pressure for filtration. However, how Piezo is involved in kidney function and in maintaining the slit diaphragm filtration structure is not clear.
We used pericardial nephrocytes, filtration kidney cells with striking structural and functional similarities to human podocytes, in a loss-of-function model (mutant and knockdown) to study the roles of Piezo in nephrocyte filtration and function.
was highly expressed at the invaginated membranes (lacuna channels) of nephrocytes. A loss-of-function mutant showed significant nephrocyte functional decline. Nephrocyte-specific silencing of Piezo showed disruption of the slit diaphragm filtration structure and significant functional defects. Electron microscopy showed that silencing Piezo in nephrocytes led to reduced slit diaphragm density and abnormal shape of lacuna channels. Moreover, the Piezo-deficient nephrocytes showed internalized slit diaphragm component proteins, reduced autophagy, increased endoplasmic reticulum stress, and reduced calcium influx.
Together, our findings suggest that Piezo plays an important role in the calcium homeostasis of nephrocytes and is required for maintaining nephrocyte function and the slit diaphragm filtration structure.
以检测机械压力而闻名的Piezo通道，被发现表达于肾细胞的腔隙通道膜上。Piezo功能丧失导致肾细胞功能障碍，包括裂孔隔膜结构破坏和腔隙通道形态改变。Piezo缺乏导致裂孔隔膜蛋白内化、自噬减少、内质网应激增加以及钙稳态受损。
该基因编码一种负责感知压力的高度保守的细胞膜蛋白。肾小球肾和裂孔隔膜过滤结构依赖压力进行过滤。然而，Piezo如何参与肾脏功能以及维持裂孔隔膜过滤结构尚不清楚。
我们在功能丧失模型（突变体和敲低）中使用心包肾细胞，这是一种与人类足细胞具有显著结构和功能相似性的过滤肾细胞，以研究Piezo在肾细胞过滤和功能中的作用。
Piezo在肾细胞的内陷膜（腔隙通道）上高度表达。功能丧失突变体显示肾细胞功能显著下降。Piezo的肾细胞特异性沉默显示裂孔隔膜过滤结构破坏和显著的功能缺陷。电子显微镜显示，肾细胞中Piezo沉默导致裂孔隔膜密度降低和腔隙通道形状异常。此外，Piezo缺陷的肾细胞显示裂孔隔膜成分蛋白内化、自噬减少、内质网应激增加以及钙内流减少。
总之，我们的研究结果表明，Piezo在肾细胞的钙稳态中起重要作用，并且是维持肾细胞功能和裂孔隔膜过滤结构所必需的。
