Diabetes research and clinical practice · 2025
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.
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Conserva Francesca, Pesce Francesco, Cinefra Claudia, Marvulli Tommaso Maria, Bari Ighli Di, Stasi Alessandra, Faienza Maria Felicia, Rossini Michele, Montinaro Adriano, Squiccimarro Elena, Sclavo Giorgia, Schirinzi Annalisa, Serio Francesca Di, Nair Viji, Fermin Damian, Menon Rajasree, Otto Edgar, Sallustio Fabio, Gallone Anna, Stallone Giovanni, Zaza Gianluigi, Laviola Luigi, Fiorentino Marco, Giorgino Francesco, Gomez Maria F, Kretzler Matthias, Gesualdo Loreto, Pontrelli Paola
Аннотация
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.
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.