Hypermethylation leads to the loss of HOXA5, resulting in JAG1 expression and NOTCH signaling contributing to kidney fibrosis,Kidney International

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Hypermethylation leads to the loss of HOXA5, resulting in JAG1 expression and NOTCH signaling contributing to kidney fibrosis
Kidney International ( IF 14.8 ) Pub Date : 2024-03-21 , DOI: 10.1016/j.kint.2024.02.023
Xiao Xiao ₁ , Wei Wang ₂ , Chunyuan Guo ₃ , Jiazhu Wu ₄ , Sheng Zhang ₅ , Huidong Shi ₆ , Sangho Kwon ₇ , Jiankang Chen ₇ , Zheng Dong ₈

Affiliation

Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China; Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Department of Urology, Institute of Urology, and Anhui Province Key Laboratory of Genitourinary Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Department of Dermatology, Shanghai Skin Disease Hospital, and Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China; Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Spine Surgery and Musculoskeletal Tumor, Zhongnan Hospital of Wuhan University, Wuhan, China.
Cancer Center, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, USA.
Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, Georgia, USA.

Epigenetic regulations, including DNA methylation, are critical to the development and progression of kidney fibrosis, but the underlying mechanisms remain elusive. Here, we show that fibrosis of the mouse kidney was associated with the induction of DNA methyltransferases and increases in global DNA methylation and was alleviated by the DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine (5-Aza). Genome-wide analysis demonstrated the hypermethylation of 94 genes in mouse unilateral ureteral obstruction kidneys, which was markedly reduced by 5-Aza. Among these genes, was hypermethylated at its gene promoter, and this hypermethylation was associated with reduced HOXA5 expression in fibrotic mouse kidneys after ureteral obstruction or unilateral ischemia-reperfusion injury. 5-Aza prevented hypermethylation, restored HOXA5 expression, and suppressed kidney fibrosis. Downregulation of HOXA5 was verified in human kidney biopsies from patients with chronic kidney disease and correlated with the increased kidney fibrosis and DNA methylation. Kidney fibrosis was aggravated by conditional knockout of and alleviated by conditional knockin of in kidney proximal tubules of mice. Mechanistically, we found that HOXA5 repressed transcription by directly binding to its gene promoter, resulting in the suppression of JAG1-NOTCH signaling during kidney fibrosis. Thus, our results indicate that loss of HOXA5 via DNA methylation contributes to fibrogenesis in kidney diseases by inducing JAG1 and consequent activation of the NOTCH signaling pathway.

中文翻译：

高甲基化导致 HOXA5 丢失，导致 JAG1 表达和 NOTCH 信号传导，导致肾纤维化

表观遗传调控，包括 DNA 甲基化，对于肾纤维化的发生和进展至关重要，但其潜在机制仍然难以捉摸。在这里，我们发现小鼠肾脏的纤维化与 DNA 甲基转移酶的诱导和整体 DNA 甲基化的增加有关，并且可以通过 DNA 甲基转移酶抑制剂 5-Aza-2'-脱氧胞苷 (5-Aza) 来缓解。全基因组分析表明，小鼠单侧输尿管梗阻肾脏中有 94 个基因的高甲基化，5-Aza 显着降低了这种高甲基化。在这些基因中，其基因启动子被高甲基化，这种高甲基化与输尿管梗阻或单侧缺血再灌注损伤后纤维化小鼠肾脏中 HOXA5 表达的降低有关。 5-Aza 可防止高甲基化、恢复 HOXA5 表达并抑制肾纤维化。 HOXA5 的下调在慢性肾病患者的肾活检中得到证实，并与肾纤维化和 DNA 甲基化的增加相关。小鼠肾近曲小管的条件性敲除会加剧肾脏纤维化，而肾近曲小管的条件性敲入则会减轻肾脏纤维化。从机制上讲，我们发现 HOXA5 通过直接与其基因启动子结合来抑制转录，从而在肾纤维化过程中抑制 JAG1-NOTCH 信号传导。因此，我们的结果表明，通过 DNA 甲基化导致 HOXA5 丢失，通过诱导 JAG1 并随后激活 NOTCH 信号通路，从而促进肾脏疾病的纤维形成。

更新日期：2024-03-21

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