Rojas-Canales Darling M, Wong Soon Wei, Tucker Elise J, Fedele Anthony O, McNicholas Kym, Mehdorn Anne-Sophie, Gleadle Jonathan M
Department of Renal Medicine, Southern Adelaide Local Health Network, Flinders Medical Centre, Bedford Park, SA, Australia.
Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Adelaide, SA, Australia.
iScience. 2024 Jul 27;27(9):110608. doi: 10.1016/j.isci.2024.110608. eCollection 2024 Sep 20.
Following kidney removal, the remaining kidney enlarges and increases its function. The mechanism and signals driving this compensatory kidney hypertrophy and the enlargement of its constituent kidney cells remains elusive. RNA-seq studies in mice undergoing hypertrophy 24, 48, and 72 h following nephrectomy were undertaken to understand the early transcriptional changes. This revealed substantial enhancement of cholesterol biosynthesis pathways, increases in mitochondrial gene expression and cell cycle perturbations. Single nuclei RNA-seq delineated cell specific changes at 24 h post nephrectomy and showed that sterol binding protein 2 (SREBP2) activity increases in medullary thick ascending limb cells in keeping with promotion of cholesterol synthesis. Cultured renal tubular cells were examined for insulin-like growth factor-1 (IGF-1) stimulated hypertrophy and SREBP2 was found to be required for increase in cell size. This work describes the early cell specific growth pathways mediating cellular and kidney hypertrophy with an intriguing role for cholesterol synthesis.
肾脏切除后，剩余的肾脏会增大并增强其功能。驱动这种代偿性肾脏肥大及其组成肾细胞增大的机制和信号仍然不清楚。为了了解早期转录变化，对肾切除术后24、48和72小时经历肥大的小鼠进行了RNA测序研究。这揭示了胆固醇生物合成途径的显著增强、线粒体基因表达的增加和细胞周期紊乱。单核RNA测序描绘了肾切除术后24小时细胞特异性变化，并表明髓袢升支粗段细胞中固醇调节元件结合蛋白2（SREBP2）活性增加，这与胆固醇合成的促进一致。对培养的肾小管细胞进行胰岛素样生长因子-1（IGF-1）刺激的肥大检测，发现SREBP2是细胞大小增加所必需的。这项工作描述了介导细胞和肾脏肥大的早期细胞特异性生长途径，胆固醇合成在其中发挥了有趣的作用。
