Nephrology Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Policlinico, Italy.
J Am Soc Nephrol. 2012 May;23(5):814-24. doi: 10.1681/ASN.2011060567. Epub 2012 Feb 23.
Aberrant O-glycosylation in the hinge region of IgA1 characterizes IgA nephropathy. The mechanisms underlying this abnormal glycosylation are not well understood, but reduced expression of the enzyme core 1, β1,3-galactosyltransferase 1 (C1GALT1) may contribute. In this study, high-throughput microRNA (miRNA) profiling identified 37 miRNAs differentially expressed in PBMCs of patients with IgA nephropathy compared with healthy persons. Among them, we observed upregulation of miR-148b, which potentially targets C1GALT1. Patients with IgA nephropathy exhibited lower C1GALT1 expression, which negatively correlated with miR-148b expression. Transfection of PBMCs from healthy persons with a miR-148b mimic reduced endogenous C1GALT1 mRNA levels threefold. Conversely, loss of miR-148b function in PBMCs of patients with IgA nephropathy increased C1GALT1 mRNA and protein levels to those observed in healthy persons. Moreover, we found that upregulation of miR-148b directly correlated with levels of galactose-deficient IgA1. In vitro, we used an IgA1-producing cell line to confirm that miR-148b modulates IgA1 O-glycosylation and the levels of secreted galactose-deficient IgA1. Taken together, these data suggest a role for miRNAs in the pathogenesis of IgA nephropathy. Abnormal expression of miR-148b may explain the aberrant glycosylation of IgA1, providing a potential pharmacologic target for IgA nephropathy.
IgA 肾病的特征是 IgA1 铰链区的异常糖基化。这种异常糖基化的机制尚不清楚，但核心 1 酶、β1,3-半乳糖基转移酶 1（C1GALT1）的表达减少可能与之相关。在这项研究中，高通量 microRNA（miRNA）谱分析鉴定出 IgA 肾病患者与健康人相比，PBMC 中 37 种 miRNA 表达差异。其中，我们观察到 miR-148b 的上调，其可能靶向 C1GALT1。IgA 肾病患者的 C1GALT1 表达降低，与 miR-148b 的表达呈负相关。将健康人 PBMC 转染 miR-148b 模拟物可使内源性 C1GALT1 mRNA 水平降低三倍。相反，在 IgA 肾病患者的 PBMC 中丧失 miR-148b 功能会增加 C1GALT1 mRNA 和蛋白水平，使其达到健康人的水平。此外，我们发现 miR-148b 的上调与缺乏半乳糖的 IgA1 水平直接相关。在体外，我们使用产生 IgA1 的细胞系证实 miR-148b 调节 IgA1 O-糖基化和分泌缺乏半乳糖的 IgA1 的水平。总之，这些数据表明 miRNA 在 IgA 肾病发病机制中的作用。miR-148b 的异常表达可能解释了 IgA1 的异常糖基化，为 IgA 肾病提供了一个潜在的药物靶点。
