Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Piazza G. Cesare, Bari 11 70124, Italy.
Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy.
Eur J Intern Med. 2023 Dec;118:108-117. doi: 10.1016/j.ejim.2023.07.045. Epub 2023 Aug 5.
Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis and the role of IL-6 in pathogenesis is becoming increasingly important. A recent whole genome DNA methylation screening in IgAN patients identified a hypermethylated region comprising the non-coding RNA Vault RNA 2-1 (VTRNA2-1) that could explain the high IL-6 levels.
The pathway leading to IL-6 secretion controlled by VTRNA2-1, PKR, and CREB was analyzed in peripheral blood mononuclear cells (PBMCs) isolated from healthy subjects (HS), IgAN patients, transplanted patients with or without IgAN. The role of double and single-strand RNA in controlling the pathway was investigated.
VTRNA2-1 was downregulated in IgAN compared to HS and in transplanted IgAN patients (TP-IgAN) compared to non-IgAN transplanted (TP). The loss of the VTRNA2-1 natural restrain in IgAN patients caused PKR hyperphosphorylation, and consequently the activation of CREB by PKR, which, in turn, led to high IL-6 production, both in IgAN and in TP-IgAN patients. IL-6 levels could be decreased by the PKR inhibitor imoxin. In addition, PKR is normally activated by bacterial and viral RNA, and we found that both the RNA poly(I:C), and the COVID-19 RNA-vaccine stimulation significantly increased the IL-6 levels in PBMCs from HS but had an opposite effect in those from IgAN patients.
The discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide a novel approach to treating the disease and may be useful for the development of precision nephrology and personalized therapy by checking the VTRNA2-1 methylation level in IgAN patients.
免疫球蛋白 A 肾病（IgAN）是最常见的原发性肾小球肾炎，IL-6 在发病机制中的作用变得越来越重要。最近对 IgAN 患者的全基因组 DNA 甲基化筛选发现了一个高甲基化区域，该区域包含非编码 RNA Vault RNA 2-1（VTRNA2-1），可解释 IL-6 水平升高的原因。
在从健康受试者（HS）、IgAN 患者和移植患者（有无 IgAN）分离的外周血单核细胞（PBMC）中分析了由 VTRNA2-1、PKR 和 CREB 控制的导致 IL-6 分泌的途径。研究了双链和单链 RNA 控制该途径的作用。
与 HS 相比，IgAN 患者的 VTRNA2-1 下调，与非 IgAN 移植患者（TP）相比，移植 IgAN 患者（TP-IgAN）的 VTRNA2-1 下调。IgAN 患者中 VTRNA2-1 的天然抑制丧失导致 PKR 过度磷酸化，进而导致 CREB 被 PKR 激活，这反过来又导致 IgAN 和 TP-IgAN 患者的 IL-6 产生增加。PKR 抑制剂 imoxin 可降低 IL-6 水平。此外，PKR 通常被细菌和病毒 RNA 激活，我们发现 RNA 多聚（I：C）和 COVID-19 RNA 疫苗均能显著增加 HS PBMC 中的 IL-6 水平，但对 IgAN 患者的 PBMC 则有相反的作用。
在 IgAN 患者中发现上调的 VTRNA2-1/PKR/CREB/IL-6 途径可能为治疗该疾病提供新方法，并且通过检查 IgAN 患者的 VTRNA2-1 甲基化水平，可能对精准肾病学和个性化治疗的发展有用。
