Renal Division, Department of Medicine, Peking University First Hospital, Beijing, 100034, China.
Peking University Institute of Nephrology, Beijing, 100034, China.
J Nephrol. 2020 Jun;33(3):551-560. doi: 10.1007/s40620-019-00682-3. Epub 2019 Dec 20.
Previous studies have revealed abnormal lymphocyte subsets in IgA nephropathy (IgAN). Some microRNAs have been reported to influence T helper differentiation. Here, we explored the underlying mechanism regarding how miRNAs regulate lymphocyte subsets in IgAN.
First, miRNA and mRNA profiles in PBMCs from IgAN patients and controls were obtained by next-generation sequencing and gene expression array. The target miRNAs and mRNAs were identified through combined analysis. Then, in an independent population, we detected the expression of target miRNA in CD3 T cells and CD19 B cells. Next, we detected T helper cell subgroups and plasma IgA1 levels in another independent population and analyzed the correlations between them.
In total, 22 differentially expressed miRNAs were identified between IgAN patients and controls. Among them, microRNA-21-5p (miR-21) showed the highest expression, and SPRY1, SPRY2, and FASLG were chosen as miR-21 target genes. Then, we confirmed elevated miR-21 levels in CD3 T cells of IgAN patients. Accordingly, decreased mRNA levels of SPRY1, SPRY2, and FASLG were found, and miR-21 showed a significant negative correlation with SPRY1 levels in CD3 T cells of IgAN patients. Finally, we revealed that the proportion of Th17 cells was significantly elevated in IgAN patients and negatively correlated with SPRY1 expression. Furthermore, the proportion of Th17 cells showed a positive correlation trend with plasma IgA1 levels.
Our results suggested that in IgAN, the upregulated miR-21 expression in T lymphocytes inhibited SPRY1 expression and thereby induced Th17 polarization, which might influence the characteristic feature of IgA1 overproduction in IgAN patients.
先前的研究表明，IgA 肾病（IgAN）患者的淋巴细胞亚群存在异常。一些 microRNA 已被报道能影响 T 辅助细胞分化。在此，我们探讨了 microRNA 调节 IgAN 患者淋巴细胞亚群的潜在机制。
首先，通过下一代测序和基因表达数组获得 IgAN 患者和对照者 PBMCs 中的 microRNA 和 mRNA 谱。通过联合分析确定靶 microRNA 和 mRNA。然后，在独立的人群中，我们检测了 CD3 T 细胞和 CD19 B 细胞中靶 microRNA 的表达。接下来，在另一个独立的人群中，我们检测了 T 辅助细胞亚群和血浆 IgA1 水平，并分析了它们之间的相关性。
共鉴定出 22 个在 IgAN 患者和对照者之间差异表达的 microRNA。其中，microRNA-21-5p（miR-21）表达最高，选择 SPRY1、SPRY2 和 FASLG 作为 miR-21 的靶基因。然后，我们证实了 IgAN 患者 CD3 T 细胞中 miR-21 水平升高。相应地，发现 SPRY1、SPRY2 和 FASLG 的 mRNA 水平降低，并且 miR-21 在 IgAN 患者 CD3 T 细胞中与 SPRY1 水平呈显著负相关。最后，我们揭示了 IgAN 患者 Th17 细胞比例显著升高，与 SPRY1 表达呈负相关。此外，Th17 细胞的比例与血浆 IgA1 水平呈正相关趋势。
我们的结果表明，在 IgAN 中，T 淋巴细胞中上调的 miR-21 表达抑制了 SPRY1 的表达，从而诱导了 Th17 极化，这可能影响 IgAN 患者 IgA1 过度产生的特征。
