DOT1L protects against podocyte injury in diabetic kidney disease through phospholipase C-like 1.

IF 8.2 2区生物学 Q1 CELL BIOLOGY

Cell Communication and Signaling Pub Date : 2024-10-25 DOI:10.1186/s12964-024-01895-1

Yepeng Hu, Shu Ye, Jing Kong, Qiao Zhou, Zhe Wang, Yikai Zhang, Han Yan, Yaqiong Wang, Tiekun Li, Yi Xie, Bingbing Chen, Yiming Zhao, Tianyue Zhang, Xianan Zheng, Junjia Niu, Bibi Hu, Shengyao Wang, Zhida Chen, Chao Zheng

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Abstract

Background: Podocyte injury causes proteinuria and accelerates glomerular sclerosis during diabetic kidney disease (DKD). Disruptor of telomeric silencing 1-like (DOT1L), an evolutionarily conserved histone methyltransferase, has been reported in preventing kidney fibrosis in chronic kidney disease models. However, whether DOT1L exerts beneficial effects in diabetes induced podocyte injury and the underlying molecular mechanisms need further exploration.

Methods: The expression of DOT1L was confirmed by Western blotting in MPC-5 cells and cortex of kidney from db/db mice, as well as immunofluorescence staining in human renal biopsy samples. The effect of DOT1L on podocyte injury was obtained using MPC-5 cells and db/db mice. The potential target genes regulated by DOT1L was measured by RNA-sequencing. Then, a series of molecular biological experiments was performed to investigate the regulation of PLCL1 by DOT1L in MCP-5 cells and db/db mice. Lipid accumulation was assessed by UPLC-MS/MS analysis and Oil Red O staining.

Results: DOT1L expression was significantly declined in high glucose (HG)-treated MPC-5 cells, podocyte regions of kidney tissues from db/db mice and human renal biopsy samples. Subsequent investigations revealed that upregulation of DOT1L ameliorated HG-induced cell apoptosis in MPC-5 cells as well as primary podocytes. Furthermore, podocyte-specific DOT1L overexpression inhibited diabetic podocyte injury in db/db mice. Mechanistically, we revealed that DOT1L upregulated phospholipase C-like 1 (PLCL1) expression by mediating H3K79me2 at its promoter and PLCL1 silencing suppressed the protective role of DOT1L on podocyte injury. Moreover, DOT1L improved diabetes induced abnormal fatty acid metabolism in podocytes and PLCL1 knockdown reversed its protective effects.

Conclusions: Taken together, our results indicate that DOT1L protects podocyte injury via PLCL1-mediated fatty acid metabolism and provides new insights into the therapeutic target of DKD.

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DOT1L 通过磷脂酶 C 样 1 保护糖尿病肾病中的荚膜细胞免受损伤。

背景：在糖尿病肾病（DKD）期间，荚膜细胞损伤会导致蛋白尿并加速肾小球硬化。据报道，端粒沉默1样破坏者（DOT1L）是一种进化保守的组蛋白甲基转移酶，可在慢性肾病模型中预防肾脏纤维化。然而，DOT1L是否对糖尿病诱导的荚膜细胞损伤有益处及其潜在的分子机制还需要进一步探讨：方法：通过Western印迹在MPC-5细胞和db/db小鼠肾脏皮质中证实了DOT1L的表达，并在人肾活检样本中进行了免疫荧光染色。利用 MPC-5 细胞和 db/db 小鼠研究了 DOT1L 对荚膜损伤的影响。通过 RNA 序列测定了 DOT1L 调控的潜在靶基因。然后，进行了一系列分子生物学实验，研究 DOT1L 在 MCP-5 细胞和 db/db 小鼠中对 PLCL1 的调控。通过UPLC-MS/MS分析和油红O染色评估脂质积累：结果：DOT1L在高糖（HG）处理的MPC-5细胞、db/db小鼠肾组织的荚膜细胞区域和人类肾活检样本中的表达量明显下降。随后的研究发现，上调 DOT1L 可改善 HG 诱导的 MPC-5 细胞和原代荚膜细胞凋亡。此外，荚膜细胞特异性 DOT1L 的过表达抑制了 db/db 小鼠的糖尿病荚膜细胞损伤。从机理上讲，我们发现 DOT1L 通过介导启动子上的 H3K79me2 上调磷脂酶 C 样 1（PLCL1）的表达，而 PLCL1 的沉默抑制了 DOT1L 对荚膜细胞损伤的保护作用。此外，DOT1L 可改善糖尿病诱导的荚膜细胞脂肪酸代谢异常，而 PLCL1 的敲除可逆转其保护作用：综上所述，我们的研究结果表明，DOT1L 通过 PLCL1 介导的脂肪酸代谢保护荚膜细胞损伤，并为 DKD 的治疗靶点提供了新的见解。

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

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.