HDAC9-mediated deacetylation of CALML6 promotes excessive proliferation of glomerular mesangial cells in IgA nephropathy.

IF 2.2 4区医学 Q2 UROLOGY & NEPHROLOGY Clinical and Experimental Nephrology Pub Date : 2025-01-21 DOI:10.1007/s10157-024-02620-5

Xingxing Zhuang, Fei Xiao, Feihu Chen, Shoudong Ni

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Abstract

Purpose: This study seeks to investigate the fundamental molecular processes through which histone deacetylase 9 (HDAC9) governs the proliferation of glomerular mesangial cells in the context of immunoglobulin A nephropathy (IgAN) and to identify novel targets for clinical research on IgAN.

Methods: Data from high-throughput RNA sequencing for IgAN were procured from the Gene Expression Omnibus database to assess the expression profiles and clinical diagnostic significance of histone deacetylase family proteins (HDACs). Blood samples from 20 IgAN patients were employed in RT-qPCR analysis, and the spearman linear regression method was utilized to analyze the clinical correlation. The proliferation of glomerular mesangial cells (GMCs) under the influence of HDAC9 was examined using the 5-ethynyl-2'-deoxyuridine (EdU) assay. Proteins interacting with HDAC9 were predicted utilizing the STRING database. Immunoprecipitation and protein immunoblotting employing anti-acetylated lysine antibodies were conducted to determine the acetylation status of calmodulin-like protein 6 (CALML6).

Results: Analysis of the GSE141295 dataset revealed a significant upregulation of HDAC9 expression in IgAN and the results of RT-qPCR demonstrated a substantial increase in HDAC9 expression in IgAN patients. Receiver operating characteristic (ROC) analysis indicated that the area under the curve (AUC) value for HDAC9 were 0.845 and Spearman correlation analysis showed that HDAC9 expression was positively correlated with blood levels of blood urea nitrogen (BUN) and serum creatinine (Crea). The EdU cell proliferation assay indicated that HDAC9 facilitated the excessive proliferation of GMCs. The STRING database and recovery experiments identified CALML6 as a downstream effector of HDAC9 in controlling abnormal GMC multiplication. Co-immunoprecipitation assays demonstrated that HDAC9 modulates CALML6 expression through acetylation modification.

Conclusion: HDAC9 is markedly upregulated in IgAN, and it mediates the excessive proliferation of GMCs by regulating the deacetylation of CALML6.

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hdac9介导的CALML6去乙酰化促进IgA肾病肾小球系膜细胞过度增殖。

目的：本研究旨在探讨组蛋白去乙酰化酶9 （HDAC9）在免疫球蛋白A肾病（IgAN）背景下控制肾小球系膜细胞增殖的基本分子过程，并为IgAN的临床研究确定新的靶点。方法：从Gene Expression Omnibus数据库获取IgAN的高通量RNA测序数据，评估组蛋白去乙酰化酶家族蛋白（histone deacetylase family protein, hdac）的表达谱和临床诊断意义。采用20例IgAN患者的血液样本进行RT-qPCR分析，采用spearman线性回归方法分析临床相关性。采用5-乙基-2′-脱氧尿苷（EdU）法检测HDAC9对肾小球系膜细胞（GMCs）增殖的影响。利用STRING数据库预测与HDAC9相互作用的蛋白。采用抗乙酰化赖氨酸抗体进行免疫沉淀和蛋白免疫印迹检测calmodulin-like protein 6 （CALML6）的乙酰化状态。结果：对GSE141295数据集的分析显示，IgAN患者中HDAC9表达显著上调，RT-qPCR结果显示，IgAN患者中HDAC9表达显著增加。受试者工作特征（ROC）分析显示HDAC9的曲线下面积（AUC）值为0.845，Spearman相关分析显示HDAC9的表达与血尿素氮（BUN）、血清肌酐（Crea）水平呈正相关。EdU细胞增殖实验表明，HDAC9促进了gmc的过度增殖。STRING数据库和恢复实验发现，CALML6是HDAC9的下游效应因子，参与控制异常GMC增殖。共免疫沉淀实验表明，HDAC9通过乙酰化修饰调节CALML6的表达。结论：HDAC9在IgAN中明显上调，并通过调节CALML6的去乙酰化介导gmc的过度增殖。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Experimental Nephrology UROLOGY & NEPHROLOGY-

CiteScore

4.10

自引率

4.30%

发文量

135

审稿时长

4-8 weeks

期刊介绍： Clinical and Experimental Nephrology is a peer-reviewed monthly journal, officially published by the Japanese Society of Nephrology (JSN) to provide an international forum for the discussion of research and issues relating to the study of nephrology. Out of respect for the founders of the JSN, the title of this journal uses the term “nephrology,” a word created and brought into use with the establishment of the JSN (Japanese Journal of Nephrology, Vol. 2, No. 1, 1960). The journal publishes articles on all aspects of nephrology, including basic, experimental, and clinical research, so as to share the latest research findings and ideas not only with members of the JSN, but with all researchers who wish to contribute to a better understanding of recent advances in nephrology. The journal is unique in that it introduces to an international readership original reports from Japan and also the clinical standards discussed and agreed by JSN.