KL (klotho) levels decline with age, which is an important mechanistic driver of aging. KL gene deficiency is associated with hypertension. The purpose of this study is to investigate the potential role of H3K27me3 (histone 3 lysine [K] 27 trimethylation) in the regulation of KL gene expression and examine the related molecular pathways that may drive kidney cell aging. Kidneys were collected from 6-month-old WT (wild type; young WT), 30-month-old WT (aged WT), and 6- (young) and 20-month-old (aged) KL mutant mice, respectively. We demonstrated that the H3K27me3 level was increased in kidneys of aged WT and KL mutant mice versus young WT mice. Elevation of H3K27me3 levels was likely due to downregulation of the H3K27 (histone H3 Lys 27)-specific demethylase JMJD3 (the Jumonji domain containing-3) in the aged kidneys. Inhibition of PRC2 (polycomb repressive complex C2; histone trimethyltransferase) decreased the H3K27me3 levels leading to an increase in the expression of KL in cultured primary renal tubule cells assessed by Western blot and KL promoter activity assays. The chromatin immunoprecipitation qPCR assay revealed that H3K27me3 was physically associated with the KL promoter region. Furthermore, aging impaired the SGK1 (serum- and glucocorticoid-induced protein kinase 1)/FOXO3a (the forkhead box class O 3a) signaling leading to upregulation of p53 and p16 (aging markers) in the kidney of aged WT mice. KL may regulate the SGK1/FOXO3 signaling, which was decreased due to KL deficiency. Thus, aging-associated downregulation of KL gene expression may be partly attributed to upregulation of H3K27me3 levels. Downregulation of KL may impair the SGK1/FOXO3 signaling contributing to kidney cell aging.

中文翻译：

---

KL (Klotho) 通过 H3K27me3（组蛋白 3 赖氨酸 [K] 27 三甲基化）在肾小管细胞中的表观遗传调控

KL (klotho) 水平随着年龄的增长而下降，这是衰老的重要机制驱动因素。KL基因缺陷与高血压有关。本研究的目的是研究 H3K27me3（组蛋白 3 赖氨酸 [K] 27 三甲基化）在 KL 基因表达调控中的潜在作用，并检查可能驱动肾细胞衰老的相关分子途径。肾脏分别从 6 个月大的 WT（野生型；年轻 WT）、30 个月大的 WT（老年 WT）和 6 个月大（年轻）和 20 个月大（老年）KL 突变小鼠中收集。我们证明，与年轻的 WT 小鼠相比，老年 WT 和 KL 突变小鼠的肾脏中的 H3K27me3 水平增加。H3K27me3 水平的升高可能是由于衰老肾脏中 H3K27（组蛋白 H3 Lys 27）特异性去甲基化酶 JMJD3（含 Jumonji 结构域-3）的下调所致。抑制PRC2（多梳抑制复合物C2；组蛋白三甲基转移酶）会降低H3K27me3 水平，导致培养的原代肾小管细胞中KL 的表达增加，经Western 印迹和KL 启动子活性测定评估。染色质免疫沉淀 qPCR 分析显示 H3K27me3 与 KL 启动子区域物理相关。此外，衰老会损害 SGK1（血清和糖皮质激素诱导的蛋白激酶 1）/FOXO3a（叉头盒 O 3a 类）信号，导致老年 WT 小鼠肾脏中 p53 和 p16（衰老标志物）的上调。KL 可能调节 SGK1/FOXO3 信号，由于 KL 缺陷，SGK1/FOXO3 信号减弱。因此，与衰老相关的 KL 基因表达下调可能部分归因于 H3K27me3 水平的上调。