Mechanisms underlying the pro gression of diabetic kidney disease to ESKD are not fully understood.

We performed global microRNA (miRNA) analysis on plasma from two cohorts consisting of 375 individuals with type 1 and type 2 diabetes with late diabetic kidney disease, and targeted proteomics analysis on plasma from four cohorts consisting of 746 individuals with late and early diabetic kidney disease. We examined structural lesions in kidney biopsy specimens from the 105 individuals with early diabetic kidney disease. Human umbilical vein endothelial cells were used to assess the effects of miRNA mimics or inhibitors on regulation of candidate proteins.

In the late diabetic kidney disease cohorts, we identified 17 circulating miRNAs, represented by four exemplars (miR-1287-5p, miR-197-5p, miR-339-5p, and miR-328-3p), that were strongly associated with 10-year risk of ESKD. These miRNAs targeted proteins in the axon guidance pathway. Circulating levels of six of these proteins—most notably, EFNA4 and EPHA2—were strongly associated with 10-year risk of ESKD in all cohorts. Furthermore, circulating levels of these proteins correlated with severity of structural lesions in kidney biopsy specimens. In contrast, expression levels of genes encoding these proteins had no apparent effects on the lesions. In in vitro experiments, mimics of miR-1287-5p and miR-197-5p and inhibitors of miR-339-5p and miR-328-3p upregulated concentrations of EPHA2 in either cell lysate, supernatant, or both.

This study reveals novel mechanisms involved in progression to ESKD and points to the importance of systemic factors in the development of diabetic kidney disease. Some circulating miRNAs and axon guidance pathway proteins represent potential targets for new therapies to prevent and treat this condition.

糖尿病肾病进展为 ESKD 的潜在机制尚不完全清楚。

我们对来自 375 名 1 型和 2 型糖尿病晚期糖尿病肾病患者的两个队列的血浆进行了全局 microRNA (miRNA) 分析，并对来自 746 名晚期和早期糖尿病肾病患者的四个队列的血浆进行了靶向蛋白质组学分析. 我们检查了 105 名早期糖尿病肾病患者肾活检标本的结构性病变。人脐静脉内皮细胞用于评估 miRNA 模拟物或抑制剂对候选蛋白质调节的影响。

在晚期糖尿病肾病队列中，我们鉴定了 17 种循环 miRNA，以四个样本（miR-1287-5p、miR-197-5p、miR-339-5p 和 miR-328-3p）为代表，它们与糖尿病肾病密切相关ESKD 的 10 年风险。这些 miRNA 靶向轴突导向通路中的蛋白质。其中六种蛋白质的循环水平——最著名的是 EFNA4 和 EPHA2——与所有队列中 10 年的 ESKD 风险密切相关。此外，这些蛋白质的循环水平与肾活检标本中结构性病变的严重程度相关。相反，编码这些蛋白质的基因的表达水平对病变没有明显影响。在体外在实验中，miR-1287-5p 和 miR-197-5p 的模拟物以及 miR-339-5p 和 miR-328-3p 的抑制剂上调了细胞裂解物、上清液或两者中 EPHA2 的浓度。

这项研究揭示了进展为 ESKD 的新机制，并指出了全身性因素在糖尿病肾病发展中的重要性。一些循环 miRNA 和轴突导向通路蛋白代表了预防和治疗这种疾病的新疗法的潜在靶点。