Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
Department of Nephrology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630 China.
Theranostics. 2021 Jan 1;11(6):2706-2721. doi: 10.7150/thno.48679. eCollection 2021.
The Jumonji domain containing-3 (JMJD3), a specific histone demethylase for trimethylation on histone H3 lysine 27 (H3K27me3), is associated with the pathogenesis of many diseases, but its role in renal fibrosis remains unexplored. Here we examined the role of JMJD3 and mechanisms involved in the activation of renal fibroblasts and development of renal fibrosis. Murine models of 5/6 surgical nephrectomy (SNx) and ureteral unilateral obstruction (UUO) were used to assess the effect of a specific JMJD3 inhibitor, GSKJ4, and genetic deletion of JMJD3 from FOXD1 stroma-derived renal interstitial cells on the development of renal fibrosis and activation of renal interstitial fibroblasts. Cultured rat renal interstitial fibroblasts (NRK-49F) and mouse renal tubular epithelial cells (mTECs) were also used to examine JMJD3-mediated activation of profibrotic signaling. JMJD3 and H3K27me3 expression levels were upregulated in the kidney of mice subjected to SNx 5/6 and UUO. Pharmacological inhibition of JMJD3 with GSKJ4 or genetic deletion of JMJD3 led to worsening of renal dysfunction as well as increased deposition of extracellular matrix proteins and activation of renal interstitial fibroblasts in the injured kidney. This was coincident with decreased expression of Smad7 and enhanced expression of H3K27me3, transforming growth factor β1 (TGFβ1), Smad3, Notch1, Notch3 and Jagged1. Inhibition of JMJD3 by GSK J4 or its specific siRNA also resulted in the similar responses in cultured NRK-49F and mTECs exposed to serum or TGFβ1. Moreover, JMJD3 inhibition augmented phosphorylation of AKT and ERK1/2 and . These results indicate that JMJD3 confers anti-fibrotic effects by limiting activation of multiple profibrotic signaling pathways and suggest that JMJD3 modulation may have therapeutic effects for chronic kidney disease.
组蛋白赖氨酸 27 三甲基化特异性去甲基酶 Jumonji 结构域包含蛋白 3（JMJD3），可特异性去除组蛋白 H3 赖氨酸 27 三甲基化（H3K27me3），与多种疾病的发病机制相关，但它在肾纤维化中的作用仍不清楚。本研究旨在探讨 JMJD3 及其在肾成纤维细胞激活和肾纤维化发展中的作用机制。采用 5/6 肾大部切除术（SNx）和单侧输尿管梗阻（UUO）两种小鼠模型，评估特异性 JMJD3 抑制剂 GSKJ4 和 FOXD1 基质衍生的肾间质细胞中 JMJD3 基因缺失对肾纤维化发展和肾间质成纤维细胞激活的影响。还使用培养的大鼠肾间质成纤维细胞（NRK-49F）和小鼠肾小管上皮细胞（mTECs）来研究 JMJD3 介导的促纤维化信号的激活。结果显示，SNx5/6 和 UUO 后小鼠肾脏中 JMJD3 和 H3K27me3 的表达水平上调。用 GSKJ4 抑制 JMJD3 或基因敲除 JMJD3 会导致肾功能恶化，并增加损伤肾脏中细胞外基质蛋白的沉积和肾间质成纤维细胞的激活。这与 Smad7 表达降低和 H3K27me3、转化生长因子β1（TGFβ1）、Smad3、Notch1、Notch3 和 Jagged1 表达增加一致。GSK J4 抑制 JMJD3 或其特异性 siRNA 也会导致培养的 NRK-49F 和 mTECs 暴露于血清或 TGFβ1 时产生类似的反应。此外，JMJD3 抑制增强了 AKT 和 ERK1/2 的磷酸化。这些结果表明，JMJD3 通过限制多种促纤维化信号通路的激活来发挥抗纤维化作用，并提示 JMJD3 调节可能对慢性肾病具有治疗作用。
