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KMT5A 的下调通过上调 ENO1 表达参与高糖介导的糖尿病肾病中的 EndMT。

KMT5A downregulation participated in High Glucose-mediated EndMT via Upregulation of ENO1 Expression in Diabetic Nephropathy.

机构信息

Department of Anesthesiology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

出版信息

Int J Biol Sci. 2021 Oct 3;17(15):4093-4107. doi: 10.7150/ijbs.62867. eCollection 2021.

DOI:10.7150/ijbs.62867
PMID:34803485
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8579450/
Abstract

Diabetic nephropathy (DN) has become the common and principal microvascular complication of diabetes that could lead to end-stage renal disease. It was reported endothelial-to-mesenchymal transition (EndMT) in glomeruli plays an important role in DN. Enolase1 (ENO1) and Lysine Methyltransferase 5A (KMT5A) were found to modulate epithelial-to-mesenchymal transition in some situations. In the present study, we speculated KMT5A regulates ENO1 transcript, thus participating in hyperglycemia-induced EndMT in glomeruli of DN. Our study represented vimentin, αSMA and ENO1 expression elevated, and CD31 expression decreased in glomeruli of DN participants and rats. , high glucose induced EndMT by increase of ENO1 levels. Moreover, high glucose downregulated KMT5A levels and increased regulatory factor X1 (RFX1) levels. KMT5A upregulation or si-RFX1 decreased high glucose-induced ENO1 expression and EndMT. RFX1 overexpression- or sh-KMT5A-induced EndMT was attenuated by si-ENO1. Further, the association between KMT5A and RFX1 was verified. Furthermore, histone H4 lysine20 methylation (the direct target of KMT5A) and RFX1 positioned on ENO1 promoter region. sh-KMT5A enhanced positive action of RFX1 on ENO1 promoter activity. KMT5A reduction and RFX1 upregulation were verified in glomeruli of DN patients and rats. KMT5A associated with RFX1 to modulate ENO1, thus involved in hyperglycemia-mediated EndMT in glomeruli of DN.

摘要

糖尿病肾病（DN）已成为糖尿病常见且主要的微血管并发症，可导致终末期肾病。据报道，肾小球内皮-间充质转化（EndMT）在 DN 中起重要作用。烯醇化酶 1（ENO1）和赖氨酸甲基转移酶 5A（KMT5A）在某些情况下被发现调节上皮-间充质转化。在本研究中，我们推测 KMT5A 调节 ENO1 转录本，从而参与高血糖诱导的 DN 肾小球 EndMT。我们的研究代表了 DN 患者和大鼠肾小球中波形蛋白、αSMA 和 ENO1 表达升高，CD31 表达降低。高葡萄糖通过增加 ENO1 水平诱导 EndMT。此外，高葡萄糖下调 KMT5A 水平并增加调节因子 X1（RFX1）水平。KMT5A 的上调或 si-RFX1 降低了高葡萄糖诱导的 ENO1 表达和 EndMT。RFX1 过表达或 sh-KMT5A 诱导的 EndMT 被 si-ENO1 减弱。此外，还验证了 KMT5A 和 RFX1 之间的关联。此外，组蛋白 H4 赖氨酸 20 甲基化（KMT5A 的直接靶标）和 RFX1 位于 ENO1 启动子区域。sh-KMT5A 增强了 RFX1 对 ENO1 启动子活性的正作用。在 DN 患者和大鼠的肾小球中验证了 sh-KMT5A 增强了 RFX1 对 ENO1 启动子活性的正作用。在 DN 患者和大鼠的肾小球中验证了 KMT5A 减少和 RFX1 上调。KMT5A 与 RFX1 相关，以调节 ENO1，从而参与高血糖介导的 DN 肾小球 EndMT。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56ee/8579450/a3b74c48bb82/ijbsv17p4093g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56ee/8579450/699aa59c5a8b/ijbsv17p4093g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56ee/8579450/a3b74c48bb82/ijbsv17p4093g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56ee/8579450/7d98388d9844/ijbsv17p4093g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56ee/8579450/67ebfb15c751/ijbsv17p4093g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56ee/8579450/97590ce019c5/ijbsv17p4093g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/56ee/8579450/a3b74c48bb82/ijbsv17p4093g007.jpg

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