Renal ischemia alters the transcriptomic and epigenetic profile of inflammatory genes in swine scattered tubular-like cells.
Renal ischemia alters the transcriptomic and epigenetic profile of inflammatory genes in swine scattered tubular-like cells.
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DOI：
10.1042/cs20230555
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发表时间：
2023-08-31
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影响因子：
--
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中科院分区：
文献类型：
--
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分散的肾小管样细胞（STC）是分化的肾小管细胞，其在从缺血性损伤恢复期间去分化以修复其他损伤的肾细胞。肾动脉狭窄（RAS），往往与慢性炎症损伤，损害的完整性和功能的STC，但其潜在的机制仍然未知。我们假设RAS改变了猪STC中炎症基因的转录组学和表观遗传学特征。在RAS或假手术10周后从猪肾收获STC（各n=6）。使用高通量mRNA测序（seq）分析炎症基因的STC mRNA谱，并通过DNA免疫沉淀和下一代测序（MeDIP-seq）（各n=3）分析其DNA甲基化（5 mC）和羟甲基化（5 hmC）谱，然后进行整合（mRNA-seq/MeDIP-seq）分析。随后在表观遗传（Bobcat 339）调节之前和之后体外评估候选差异表达（DE）基因和常见促炎蛋白的STC蛋白表达。mRNA-seq鉴定了57个炎性基因在RAS-STC中相对于正常STC上调（>1.4或<0.7倍，p<0.05），其中14%在RAS-STC中相对于正常STC分别表现出较低的5 mC和较高5%的5 hmC水平。RAS-STC中的炎症基因和蛋白表达高于正常STC，但在表观遗传调节后正常化。这些观察结果突出了这种肾脏内源性修复系统的新调节机制，并支持开发表观遗传或抗炎疗法，以保护RAS患者STC的修复能力。
Scattered tubular-like cells (STCs) are differentiated renal tubular cells that during recovery from ischemic injury dedifferentiate to repair other injured renal cells. Renal artery stenosis (RAS), often associated with chronic inflammatory injury, compromises the integrity and function of STCs, but the underlying mechanisms remain unknown. We hypothesized that RAS alters the transcriptomic and epigenetic profile of inflammatory genes in swine STCs. STCs were harvested from pig kidneys after 10 weeks of RAS or sham (n=6 each). STC mRNA profiles of inflammatory genes were analyzed using high-throughput mRNA-sequencing (seq) and their DNA methylation (5mC) and hydroxymethylation (5hmC) profiles by DNA immunoprecipitation and next-generation sequencing (MeDIP-seq) (n=3 each), followed by an integrated (mRNA-seq/MeDIP-seq) analysis. STC protein expression of candidate differentially expressed (DE) genes and common pro-inflammatory proteins were subsequently assessed in-vitro before and after epigenetic (Bobcat339) modulation. mRNA-seq identified 57 inflammatory genes upregulated in RAS-STCs versus Normal-STCs (>1.4 or <0.7-fold, p<0.05), of which 14% exhibited lower 5mC and 5% higher 5hmC levels in RAS-STCs versus Normal-STCs, respectively. Inflammatory gene and protein expression was higher in RAS-STCs compared to Normal-STCs but normalized after epigenetic modulation. These observations highlight a novel modulatory mechanism of this renal endogenous repair system and support development of epigenetic or anti-inflammatory therapies to preserve the reparative capacity of STCs in individuals with RAS.
影响因子：
7.5
作者：
Eirin A;Zhu XY;Ferguson CM;Riester SM;van Wijnen AJ;Lerman A;Lerman LO
通讯作者：
Lerman LO
影响因子：
5.2
作者：
Zhu, Xiang-Yang;Urbieta-Caceres, Victor;Krier, James D.;Textor, Stephen C.;Lerman, Amir;Lerman, Lilach O.
通讯作者：
Lerman, Lilach O.