Association between urinary extracellular vesicle proteome and early detection of diabetic nephropathy in type 2 diabetes
DOI:
https://doi.org/10.65327/kidneys.v14i4.568Keywords:
Diabetic nephropathy; Extracellular vesicles; Hypoxia; Proteomics; miRNAAbstract
Early detection of diabetic nephropathy (DN) remains limited by low-sensitivity clinical markers such as albuminuria and eGFR. Hypoxia-driven injury in proximal tubular epithelial cells (PTECs) is recognized as an early event in DN, yet its relationship to urinary extracellular vesicle (EV) cargo is not fully defined. Identifying hypoxia-responsive proteins and miRNAs released by PTECs may provide a mechanistic foundation for urinary EV–based early biomarkers. Secondary multi-omic datasets were analyzed, comprising matched PTEC hypoxia proteomic (377 proteins) and miRNA profiles (defined and novel miRNAs) collected from apical and basal compartments. After stringent quality filtering and normalization, differential expression analysis was conducted using log₂ fold change thresholds (|log₂FC| ≥ 1) and FDR ≤ 0.05. Significant features were grouped into four hypoxia-responsive signatures: apical and basal upregulated proteins, and apical and basal upregulated miRNAs. Functional enrichment (GO/KEGG) and extracellular vesicle annotation were performed to identify biologically relevant pathways and potential urinary EV biomarkers. A total of 112 apical and 94 basal proteins, as well as 51 apical and 38 basal miRNAs, were significantly altered under hypoxia. Dominant pathways included HIF-1 signaling, glycolysis, oxidative stress response, vesicle-mediated transport, and extracellular matrix remodeling. Several hypoxia-induced proteins (e.g., ENO1, RAB27A, HSP90B1) and miRNAs (miR-210, miR-29 family, and novel hypoxia-responsive candidates) overlapped with known EV components, supporting their potential detectability in urine. Hypoxia induces coordinated proteomic and miRNA remodeling in PTECs, generating EV-relevant molecular signatures with strong mechanistic relevance to early DN. These findings offer a robust foundation for developing non-invasive urinary EV biomarkers capable of detecting tubular stress before clinical decline.
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Copyright (c) 2025 Ms. Neepa Patel, Dr. Prashant M. Modi, Ninad Nangare, Dr Abhishek Anand, Charumathi Dhanushkodi, Dr Kumar Sambhav
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