Circulating Ephrin-Eph Signaling Reflects Interstitial Fibrosis and Tubular Atrophy in Diabetic Kidney Disease.

BACKGROUND: Diabetic kidney disease (DKD) is characterized by heterogeneous renal histological patterns, among which interstitial fibrosis and tubular atrophy (IFTA) is a key determinant of patient outcomes and treatment response. However, blood biomarkers reflecting IFTA burden remain unestablished. METHODS: We conducted SomaScan-based blood proteomic profiling in Korean patients with biopsy-confirmed diabetic nephropathy from Seoul National University Hospital (SNUH-DN; n = 129). Linear regression analyses were used to identify pathways associated with IFTA area, and those additionally upregulated compared with healthy individuals were prioritized. Findings were validated in two external cohorts with available SomaScan data and histological IFTA assessment: the Kidney Precision Medicine Project (KPMP; n = 73) and the Boston Kidney Biopsy Cohort (BKBC; n = 414). Renal expression and downstream signaling of pathway components were evaluated using human kidney multiome data from KPMP. RESULTS: In the SNUH-DN cohort, the ephrin receptor signaling pathway emerged as the top pathway both positively associated with IFTA area and upregulated in DKD patients. This association was replicated in the KPMP and BKBC cohorts. High activity of the ephrin receptor signaling pathway was also associated with a higher risk of kidney failure. Kidney tissue analyses demonstrated a higher expression of ephrin-Eph signaling components, particularly genes encoding EPHA4 and EPHB1, in diabetic kidneys. Renal expression of these genes correlated with epithelial-mesenchymal transition signatures, accompanied by downstream activation of hypoxia, JAK-STAT, and TGFβ signaling pathways across multiple kidney cell types. CONCLUSIONS: Upregulation of the ephrin receptor signaling pathway represents a robust and reproducible blood proteomic signature reflecting IFTA in DKD.