Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
J Biol Chem. 2020 Nov 27;295(48):16328-16341. doi: 10.1074/jbc.RA120.015110. Epub 2020 Sep 4.
Acute kidney injury (AKI) is a common clinical condition associated with diverse etiologies and abrupt loss of renal function. In patients with sepsis, rhabdomyolysis, cancer, and cardiovascular disorders, the underlying disease or associated therapeutic interventions can cause hypoxia, cytotoxicity, and inflammatory insults to renal tubular epithelial cells (RTECs), resulting in the onset of AKI. To uncover stress-responsive disease-modifying genes, here we have carried out renal transcriptome profiling in three distinct murine models of AKI. We find that nerve growth factor inducible gene up-regulation is a common transcriptional stress response in RTECs to ischemia-, cisplatin-, and rhabdomyolysis-associated renal injury. The gene encodes a secretory peptide precursor protein that has critical neuroendocrine functions; however, its role in the kidneys remains unknown. Our functional studies show that RTEC-specific gene ablation exacerbates ischemia-, cisplatin-, and rhabdomyolysis-associated AKI and cisplatin-induced RTEC cell death Importantly, aggravation of cisplatin-induced renal injury caused by gene ablation is partly reversed by TLQP-21, a Vgf-derived peptide. Finally, and mechanistic studies showed that injury-induced up-regulation in RTECs is driven by the transcriptional regulator Sox9. These findings reveal a crucial downstream target of the Sox9-directed transcriptional program and identify as a stress-responsive protective gene in kidney tubular epithelial cells.
急性肾损伤（AKI）是一种常见的临床病症，与多种病因和肾功能突然丧失有关。在脓毒症、横纹肌溶解症、癌症和心血管疾病患者中，基础疾病或相关治疗干预可能导致肾管状上皮细胞（RTEC）缺氧、细胞毒性和炎症损伤，从而引发 AKI。为了揭示应激反应相关的疾病修饰基因，我们在此对三种不同的 AKI 小鼠模型进行了肾脏转录组谱分析。我们发现神经生长因子诱导基因上调是 RTEC 对缺血、顺铂和横纹肌溶解相关肾损伤的共同转录应激反应。该基因编码一种分泌肽前体蛋白，具有关键的神经内分泌功能；然而，其在肾脏中的作用尚不清楚。我们的功能研究表明，RTEC 特异性基因缺失会加重缺血、顺铂和横纹肌溶解相关的 AKI 以及顺铂诱导的 RTEC 细胞死亡。重要的是，TLQP-21（一种 Vgf 衍生的肽）部分逆转了 基因缺失引起的顺铂诱导的肾损伤加重。最后，损伤诱导的 RTEC 中 Sox9 驱动的 上调的机制研究表明。这些发现揭示了 Sox9 定向转录程序的一个关键下游靶标，并将 鉴定为肾管状上皮细胞中的应激反应性保护基因。
