血压
内分泌学
内科学
肾
钠
肾脏生理学
脱甲基酶
排泄
化学
生理学
医学
表观遗传学
生物化学
基因
有机化学
作者
Xiaobin Han,Leah Akinseye,Zhongjie Sun
出处
期刊:Hypertension
[Ovid Technologies (Wolters Kluwer)]
日期:2024-03-01
卷期号:81 (3): 541-551
标识
DOI:10.1161/hypertensionaha.123.22026
摘要
KDM6A is a specific demethylase for histone 3 lysine (K) 27 trimethylation (H3K27me3). The purpose of this study is to investigate whether KDM6A in renal tubule cells plays a role in the regulation of kidney function and blood pressure.We first crossed Ksp-Cre+/-and KDM6Aflox/flox mice for generating inducible kidney-specific deletion of KDM6A gene.Notably, conditional knockout of KDM6A gene in renal tubule cells (KDM6A-cKO) increased H3K27me3 levels which leads to a decrease in Na excretion and elevation of blood pressure. Further analysis showed that the expression of NKCC2 (Na-K-2Cl cotransporter 2) and NCC (Na-Cl cotransporters) was upregulated which contributes to impaired Na excretion in KDM6A-cKO mice. The expression of AQP2 (aquaporin 2) was also increased in KDM6A-cKO mice, which may facilitate water reabsorption in KDM6A-cKO mice. The expression of Klotho was downregulated while expression of aging markers including p53, p21, and p16 was upregulated in kidneys of KDM6A-cKO mice, indicating that deletion of KDM6A in the renal tubule cells promotes kidney aging. Interestingly, KDM6A-cKO mice developed salt-sensitive hypertension which can be rescued by treatment with Klotho. KDM6A deficiency induced salt-sensitive hypertension likely through downregulation of the Klotho/ERK (extracellular signal-regulatd kinase) signaling and upregulation of the WNK (with-no-lysine kinase) signaling.This study provides the first evidence that KDM6A plays an essential role in maintaining normal tubular function and blood pressure. Renal tubule cell specific KDM6A deficiency causes hypertension due to increased H3K27me3 levels and the resultant downregulation of Klotho gene expression which disrupts the Klotho/ERK/NCC/NKCC2 signaling.
科研通智能强力驱动
Strongly Powered by AbleSci AI