Systematic assessment of distinctive features in diabetic nephropathy reveals ACKR1 as a novel regulator
Diabetes nephropathy (DN) has a unique molecular pathogenesis different from other major glomerular diseases, but its characteristic mechanism has not yet been completely determined. The integrated meta-analysis of transcriptomic data from multiple human renal biopsy cohorts were performed. Key findings were validated in a DN mouse model, and comprehensive functional analysed in renal tubular cells. We found that the transcript profile significantly distinguish DN from IgA and membranous nephropathy. From this signature, we identified the atypical chemokine receptor (ACKR1) as a top unreported candidate gene in DN model. Overexpression of ACKR1 in renal tubular cells, particularly in co-culture with patient-derived immune cells, triggered a pathogenic program involving sustained chemokine production, chronic interferon signaling, and fibrotic execution.This study advances our understanding of DN by delineating its unique molecular pathogenesis. The identification of ACKR1 from unreported genes not only uncover it as a core component driving the progression of specific immunofibrotic in DN, but also underscores the pivotal role that overlooked targets may play, providing a novel perspective for precision treatment of DN.