Lipocalin-2 Emerges as a Core Pathogenic Mediator and Biomarker in Autosomal Dominant Tubulointerstitial Kidney...

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a group of inherited renal disorders characterized by progressive decline in kidney function, with UMOD being the most frequently mutated gene. This study aimed to delineate critical molecular pathways and candidate genes involved in ADTKD-UMOD through integrated transcriptomic profiling and experimental validation, including newly added analyses of early stage disease and human samples.

Transcriptomic datasets (GSE214491, GSE139585, GSE97093) from ADTKD-UMOD murine kidney tissues were analyzed for differentially expressed genes (DEGs) with the criteria: |log₂ fold change| ≥ 1.5 and p < 0.05. Functional enrichment was assessed by GO and KEGG analyses, and hub genes were identified using protein-protein interaction networks. Immune cell infiltration was estimated by CIBERSORT. The key candidate gene LCN2 was validated in HEK293 cells expressing mutant UMOD (C195R) by qPCR and in an expanded analysis of serum from patients with ADTKD-UMOD by ELISA.

In GSE214491 (6 mutant vs 6 wild type mice), 302 DEGs were identified at 4 months, and an additional 117 DEGs were newly characterized at 1 month, when histological disease was minimal. GSE139585 revealed 12 DEGs, and GSE97093 showed 83 and 16 DEGs in male and female cohorts, respectively. Across datasets, Lcn2 was consistently identified as a significant DEG and central hub gene and was already significantly elevated in 1-month-old ADTKD-UMOD (R186S) mice. Functional enrichment implicated pathways related to cell activation, metabolic processes, and inflammation. In UMOD (C195R)-mutant HEK293 cells, LCN2 mRNA was higher than in wild-type cells (2.95 ± 0.31 vs. 1.12 ± 0.19, p < 0.01), as were CASP1 (5.38 ± 0.95 vs. 0.48 ± 0.08, p < 0.001) and GSDME (1.69 ± 0.21 vs. 1.00 ± 0.09, p < 0.001). In human specimens, serum LCN2 protein levels were elevated in patients compared with healthy controls (4,204.06 ± 239.51 vs. 3,078.02 ± 88.41 pg/mL, p < 0.01).

LCN2 protein emerges as a reproducible biomarker and plausible pathogenic mediator across distinct UMOD mutations, with concordant evidence from mouse models, cell experiments, and patient samples, thereby providing a strengthened rationale for its further mechanistic and translational investigation in ADTKD-UMOD.