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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

Conserva, Francesca ; Pesce, Francesco ; Cinefra, Claudia ; Marvulli, Tommaso Maria ; Bari, Ighli Di ; Stasi, Alessandra ; Faienza, Maria Felicia ; Rossini, Michele ; Montinaro, Adriano and Squiccimarro, Elena , et al. (2025) In Diabetes Research and Clinical Practice 229.
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CKD in type 2 diabetes, Glycaemic control, miRNAs, Non-invasive biomarkers, Patient stratification, Personalised medicine, SNPs
in
Diabetes Research and Clinical Practice
volume
229
article number
112460
publisher
Elsevier
external identifiers
  • pmid:40934963
  • scopus:105015361102
ISSN
0168-8227
DOI
10.1016/j.diabres.2025.112460
language
English
LU publication?
yes
id
ab907f59-a041-4463-8e9c-2bfac4523a80
date added to LUP
2025-10-03 13:56:06
date last changed
2025-10-03 14:18:48
@article{ab907f59-a041-4463-8e9c-2bfac4523a80,
  abstract     = {{<p>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.</p>}},
  author       = {{Conserva, Francesca and Pesce, Francesco and Cinefra, Claudia and Marvulli, Tommaso Maria and Bari, Ighli Di and Stasi, Alessandra and Faienza, Maria Felicia and Rossini, Michele and Montinaro, Adriano and Squiccimarro, Elena and Sclavo, Giorgia and Schirinzi, Annalisa and Serio, Francesca Di and Nair, Viji and Fermin, Damian and Menon, Rajasree and Otto, Edgar and Sallustio, Fabio and Gallone, Anna and Stallone, Giovanni and Zaza, Gianluigi and Laviola, Luigi and Fiorentino, Marco and Giorgino, Francesco and Gomez, Maria F. and Kretzler, Matthias and Gesualdo, Loreto and Pontrelli, Paola}},
  issn         = {{0168-8227}},
  keywords     = {{CKD in type 2 diabetes; Glycaemic control; miRNAs; Non-invasive biomarkers; Patient stratification; Personalised medicine; SNPs}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Diabetes Research and Clinical Practice}},
  title        = {{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}},
  url          = {{http://dx.doi.org/10.1016/j.diabres.2025.112460}},
  doi          = {{10.1016/j.diabres.2025.112460}},
  volume       = {{229}},
  year         = {{2025}},
}