Severe ischemia-reperfusion injury (IRI) causes acute and chronic kidney allograft damage. As therapeutic interventions to reduce damage are limited yet, research on how to promote kidney repair has gained significant interest. To address this question, we performed genome-wide transcriptome and epigenome profiling in progenitor cells isolated from the urine of deceased (severe IRI) and living (mild IRI) donor human kidney transplants and identified LIM homeobox-1 (LHX1) as an epigenetically regulated gene whose expression depends on the IRI severity. Using a mouse model of IRI, we observed a relationship between IRI severity, LHX1 promoter hypermethylation, and LHX1 gene expression. Using functional studies, we confirmed that LHX1 expression is involved in the proliferation of epithelial tubular cells and podocyte differentiation from kidney progenitor cells. Our results provide evidence that severe IRI may reduce intrinsic mechanisms of kidney repair through epigenetic signaling.

中文翻译：

---

严重缺血再灌注损伤诱导肾移植后肾祖细胞 LHX1 表观遗传失活


严重的缺血再灌注损伤 （IRI） 会导致急性和慢性同种异体肾移植物损伤。由于减少损伤的治疗干预措施有限，因此关于如何促进肾脏修复的研究引起了人们的极大兴趣。为了解决这个问题，我们在从已故（严重 IRI）和活体（轻度 IRI）供体人肾移植的尿液中分离的祖细胞中进行了全基因组转录组和表观基因组分析，并将 LIM 同源盒-1 （LHX1） 鉴定为表观遗传调控基因，其表达取决于 IRI 的严重程度。使用 IRI 的小鼠模型，我们观察到 IRI 严重程度、LHX1 启动子高甲基化和 LHX1 基因表达之间的关系。使用功能研究，我们证实 LHX1 表达参与上皮肾小管细胞的增殖和足细胞从肾祖细胞的分化。我们的结果提供了证据表明，严重的 IRI 可能会通过表观遗传信号传导降低肾脏修复的内在机制。