A renal biopsy–anchored multi-marker signature involving AOPEP SNP-driven splicing, miR-27b-3p and glycated albumin for stratifying renal damage in type 2 diabetes

IF 7.4 3区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes research and clinical practice Pub Date : 2025-09-09 DOI:10.1016/j.diabres.2025.112460

Francesca Conserva , Francesco Pesce , Claudia Cinefra , Tommaso Maria Marvulli , Ighli Di Bari , Alessandra Stasi , Maria Felicia Faienza , Michele Rossini , Adriano Montinaro , Elena Squiccimarro , Giorgia Sclavo , Annalisa Schirinzi , Francesca Di Serio , Viji Nair , Damian Fermin , Rajasree Menon , Edgar Otto , Fabio Sallustio , Anna Gallone , Giovanni Stallone , Paola Pontrelli

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引用次数: 0

Abstract

Aims

Stratifying renal damage in type 2 diabetes is challenging due to overlapping features between diabetic nephropathy (DN) and non-diabetic renal disease (NDRD). While miR-27b-3p modulates kidney fibrosis in DN through the lysine63 ubiquitination pathway, its upstream regulation and diagnostic relevance remain unclear.

Methods

In a biopsy-verified cohort of 231 chronic kidney disease (CKD) patients with and without type 2 diabetes, we investigated whether AOPEP promoter SNPs drive alternative splicing affecting intronic miR-27b-3p expression. We also assessed the diagnostic utility of combining these biomarkers with clinical parameters, such as glycated albumin (GA), to distinguish DN from NDRD.

Results

The rs10761364 minor allele was associated with reduced urinary miR-27b-3p and AOPEP splicing that excluded exons hosting the miR-23b/27b/24 cluster. This pattern, observed in vivo and under hyperglycemia in vitro, led to elevated AOPEP protein isoforms. A model combining rs10761364, GA, and urinary miR-27b-3p showed high diagnostic accuracy (AUC up to 0.93) in discriminating DN from NDRD. miR-27b-3p inversely correlated with GA, and GA-based models outperformed those using HbA1c.

Conclusion

We identify a genotype- and glucose-dependent mechanism regulating miR-27b-3p via AOPEP splicing and propose a biopsy-anchored, non-invasive biomarker panel (rs10761364, GA, miR-27b-3p) to differentiate DN from NDRD, supporting personalized nephrology care.

Abstract Image

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肾活检锚定的多标记特征，涉及AOPEP snp驱动剪接，miR-27b-3p和糖化白蛋白，用于2型糖尿病肾损害分层。

目的：由于糖尿病肾病（DN）和非糖尿病肾病（NDRD）之间的重叠特征，2型糖尿病肾损害分层具有挑战性。虽然miR-27b-3p通过赖氨酸63泛素化途径调节DN的肾纤维化，但其上游调控和诊断相关性尚不清楚。方法：在一项经活检证实的231例伴有或不伴有2型糖尿病的慢性肾脏疾病（CKD）患者队列中，我们研究了AOPEP启动子snp是否驱动影响内含子miR-27b-3p表达的选择性剪接。我们还评估了将这些生物标志物与临床参数（如糖化白蛋白（GA））相结合的诊断效用，以区分DN和NDRD。结果：rs10761364小等位基因与尿miR-27b-3p和AOPEP剪接减少相关，这排除了承载miR-23b/27b/24簇的外显子。这种模式在体内和体外高血糖状态下观察到，导致AOPEP蛋白亚型升高。rs10761364、GA和尿miR-27b-3p联合建立的模型在区分DN和NDRD方面显示出较高的诊断准确率（AUC高达0.93）。miR-27b-3p与GA呈负相关，基于GA的模型优于使用HbA1c的模型。结论：我们确定了一种基因型和葡萄糖依赖的机制，通过AOPEP剪接调节miR-27b-3p，并提出了一种活检锚定的非侵入性生物标志物面板（rs10761364， GA, miR-27b-3p）来区分DN和NDRD，支持个性化肾病护理。

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来源期刊

Diabetes research and clinical practice 医学-内分泌学与代谢

CiteScore

10.30

自引率

3.90%

发文量

862

审稿时长

32 days

期刊介绍： Diabetes Research and Clinical Practice is an international journal for health-care providers and clinically oriented researchers that publishes high-quality original research articles and expert reviews in diabetes and related areas. The role of the journal is to provide a venue for dissemination of knowledge and discussion of topics related to diabetes clinical research and patient care. Topics of focus include translational science, genetics, immunology, nutrition, psychosocial research, epidemiology, prevention, socio-economic research, complications, new treatments, technologies and therapy.