He Xian, Wang Ziming, Cheng Linxi, Wang Han, Sun Yuhua
Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, 430072, Wuhan, China.
The Innovation of Seed Design, Chinese Academy of Sciences, 430072, Wuhan, China.
Commun Biol. 2025 Jan 9;8(1):29. doi: 10.1038/s42003-025-07455-8.
The circadian clock genes are known important for kidney development, maturation and physiological functions. However, whether and how they play a role in renal regeneration remain elusive. Here, by using the single cell RNA-sequencing (scRNA-seq) technology, we investigated the dynamic gene expression profiles and cell states after acute kidney injury (AKI) by gentamicin treatment in zebrafish. The core clock genes such as per1/2 and nr1d1, which encode transcriptional repressors of the circadian system, are strongly induced in the proximal tubule epithelial cells (PTECs). By generating mutant zebrafish lines, we show that per1a and nr1d1 are required for proper renal regeneration, by facilitating the expression of renal progenitor cell (RPC) genes. In per1a and nr1d1 mutants, the expression of RPC genes and the number of RPCs were decreased, resulting in a marked delay in nephron regeneration. lima1a, which encodes a cytoskeleton binding protein that functions to negatively regulate epithelial to mesenchymal transition (EMT), is identified as the direct target of the clock proteins. Down-regulation of lima1a is associated with enhanced EMT, increased expression of cell migration- and RPC markers, and accelerated nephron regeneration. We propose that per1a and nr1d1 are important for the formation of nephrongenic RPCs by repressing lima1a. Our findings using zebrafish provide important insights into the roles of the clock genes in kidney repair.
昼夜节律时钟基因已知对肾脏发育、成熟和生理功能很重要。然而，它们是否以及如何在肾脏再生中发挥作用仍不清楚。在这里，通过使用单细胞RNA测序（scRNA-seq）技术，我们研究了斑马鱼经庆大霉素处理急性肾损伤（AKI）后的动态基因表达谱和细胞状态。核心时钟基因，如编码昼夜节律系统转录抑制因子的per1/2和nr1d1，在近端肾小管上皮细胞（PTECs）中被强烈诱导。通过生成突变斑马鱼品系，我们表明per1a和nr1d1通过促进肾祖细胞（RPC）基因的表达，对适当的肾脏再生是必需的。在per1a和nr1d1突变体中，RPC基因的表达和RPC的数量减少，导致肾单位再生明显延迟。lima1a编码一种细胞骨架结合蛋白，其功能是负向调节上皮-间质转化（EMT），被确定为时钟蛋白的直接靶点。lima1a的下调与增强的EMT、细胞迁移和RPC标志物表达增加以及加速的肾单位再生相关。我们提出，per1a和nr1d1通过抑制lima1a对肾源性RPC的形成很重要。我们使用斑马鱼的研究结果为时钟基因在肾脏修复中的作用提供了重要见解。
