Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19014, USA.
Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, 19014, USA.
Nat Commun. 2023 Feb 2;14(1):559. doi: 10.1038/s41467-023-36212-w.
Inflammation is a common feature of all forms of chronic kidney disease; however, the underlying mechanism remains poorly understood. Evolutionarily inherited endogenous retroviruses (ERVs) have the potential to trigger an immune reaction. Comprehensive RNA-sequencing of control and diseased kidneys from human and mouse disease models indicated higher expression of transposable elements (TEs) and ERVs in diseased kidneys. Loss of cytosine methylation causing epigenetic derepression likely contributes to an increase in ERV levels. Genetic deletion/pharmacological inhibition of DNA methyltransferase 1 (DNMT1) induces ERV expression. In cultured kidney tubule cells, ERVs elicit the activation of cytosolic nucleotide sensors such as RIG-I, MDA5, and STING. ERVs expressions in kidney tubules trigger RIG-I/STING, and cytokine expression, and correlate with the presence of immune cells. Genetic deletion of RIG-I or STING or treatment with reverse transcriptase inhibitor ameliorates kidney fibroinflammation. Our data indicate an important role of epigenetic derepression-induced ERV activation triggering renal fibroinflammation.
炎症是所有形式的慢性肾病的共同特征；然而，其潜在机制仍知之甚少。进化上遗传的内源性逆转录病毒 (ERVs) 有可能引发免疫反应。对来自人类和小鼠疾病模型的对照和患病肾脏的全面 RNA 测序表明，患病肾脏中转座元件 (TEs) 和 ERVs 的表达水平更高。导致表观遗传去抑制的胞嘧啶甲基化缺失可能导致 ERV 水平升高。DNA 甲基转移酶 1 (DNMT1) 的遗传缺失/药理学抑制诱导 ERV 表达。在培养的肾小管细胞中，ERVs 激活细胞质核苷酸传感器，如 RIG-I、MDA5 和 STING。肾脏肾小管中的 ERV 表达触发 RIG-I/STING 和细胞因子表达，并与免疫细胞的存在相关。RIG-I 或 STING 的基因缺失或逆转录酶抑制剂治疗可改善肾脏纤维化炎症。我们的数据表明，表观遗传去抑制诱导的 ERV 激活触发肾脏纤维化炎症的重要作用。
