HDAC3 Inhibition Improves Urinary Concentrating Defect in Hypokalaemia by Promoting AQP2 Transcription
HDAC3 Inhibition Improves Urinary Concentrating Defect in Hypokalaemia by Promoting AQP2 Transcription
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HDAC3 抑制通过促进 AQP2 转录改善低钾血症的尿液浓缩缺陷
DOI：
10.1111/apha.13802
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Li Chunling
中科院分区：
文献类型：
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作者：
Xu Long;Xie Haixia;Hu Shan;Zhao Xiaoduo;Han Mengke;Liu Qiaojuan;Feng Pinning;Wang Weidong;Li Chunling
AimThis study investigated whether enhanced histone acetylation，achieved by inhibiting histone deacetylases（HDACs），could prevent reduced aquaporin-2（AQP 2）expression during hypokalaemia.MethodsMale Wistar rats were fed a keto-free diet with or without 4-phenylbutyric acid（4-PBA）or the selective HDAC3 inhibitor RGFP966 for 4 days.结果4-PBA可增加低钾血症（HK）大鼠肾脏内髓集合管（IMCD）细胞和永生化小鼠皮质集合管（mpkCCD）细胞中AQP 2 mRNA和蛋白的表达，并伴有尿量减少和尿渗透压升高。HK大鼠肾脏内髓中乙酰化H3 K27（H3 K27 ac）蛋白的水平降低; 4-PBA可缓解这种降低。在缺钾培养基中培养的IMCD和mpkCCD细胞中H3 K27 ac水平降低。Aqp 2启动子区H3 K27 ac的降低与Aqp 2 mRNA水平的降低有关。HDAC 3蛋白表达上调mpkCCD和IMCD细胞响应钾剥夺，HDAC 3的Aqp 2启动子的结合也增加。RGFP 966增加mpkCCD细胞中H3 K27 ac和AQP 2蛋白的水平，并增强H3 K27 ac和AQP 2之间的结合。此外，RGFP 966逆转了低钾血症诱导的AQP 2和H3 K27 ac下调，并减轻了大鼠的多尿。RGFP 966增加HK大鼠肾内髓质的间质渗透压，但不影响尿cAMP水平。结论HDAC抑制剂防止钾剥夺诱导的AQP 2下调，可能是通过增强H3 K27乙酰化。
AimThis study investigated whether enhanced histone acetylation, achieved by inhibiting histone deacetylases (HDACs), could prevent decreased aquaporin‐2 (AQP2) expression during hypokalaemia.MethodsMale Wistar rats were fed a potassium‐free diet with or without 4‐phenylbutyric acid (4‐PBA) or the selective HDAC3 inhibitor RGFP966 for 4 days. Primary renal inner medullary collecting duct (IMCD) cells and immortalized mouse cortical collecting duct (mpkCCD) cells were cultured in potassium‐deprivation medium with or without HDAC inhibitors.Results4‐PBA increased the levels of AQP2 mRNA and protein in the kidney inner medullae in hypokalaemic (HK) rats, which was associated with decreased urine output and increased urinary osmolality. The level of acetylated H3K27 (H3K27ac) protein was decreased in the inner medullae of HK rat kidneys; this decrease was mitigated by 4‐PBA. The H3K27ac levels were decreased in IMCD and mpkCCD cells cultured in potassium‐deprivation medium. Decreased H3K27ac in theAqp2promoter region was associated with reducedAqp2mRNA levels. HDAC3 protein expression was upregulated in mpkCCD and IMCD cells in response to potassium deprivation, and the binding of HDAC3 to theAqp2promoter was also increased. RGFP966 increased the levels of H3K27ac and AQP2 proteins and enhanced binding between H3K27ac and AQP2 in mpkCCD cells. Furthermore, RGFP966 reversed the hypokalaemia‐induced downregulation of AQP2 and H3K27ac and alleviated polyuria in rats. RGFP966 increased interstitial osmolality in the kidney inner medullae of HK rats but did not affect urinary cAMP levels.ConclusionHDAC inhibitors prevented the downregulation of AQP2 induced by potassium deprivation, probably by enhancing H3K27 acetylation.