The dual role of ion channels in diabetic kidney disease: a translational paradigm for biomarkers and target discovery - reviews and prospects.

Abstract

The clinical heterogeneity of diabetic kidney disease (DKD) poses a major challenge to current treatment strategies. This review proposes a novel translational paradigm: viewing ion channels as dual-function entities that serve both as pathogenic mediators and as rich sources of clinically actionable biomarkers. We systematically elucidate how hyperglycemia, oxidative stress, and inflammation disrupt sodium, calcium, potassium, and chloride channel networks through interconnected pathways such as AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR), NLR family pyrin domain containing 3 (NLRP3), and PIEZO1. These disruptions not only drive renal injury but also generate a cascade of detectable molecular signals - from genomic variations and epigenetic changes to circulating protein fragments and exosomal non-coding RNAs. We review these multi-level biomarker sources and their detection platforms, including cutting-edge, minimally invasive technologies such as urinary cell-free DNA (cfDNA) methylation profiling and artificial intelligence (AI)-driven multi-omics integration. Crucially, we detail how these "channelopathy fingerprints" can be translated into clinical tools for molecular endotyping, predicting and monitoring treatment responses to established (sodium-glucose cotransporter 2 (SGLT2) inhibitors, finerenone) and emerging (transient receptor potential canonical 6 (TRPC6) inhibitors) therapies, and optimizing clinical trial designs through biomarker-driven enrichment strategies. Finally, we propose a phased, multi-stakeholder roadmap from biomarker discovery to clinical integration, aiming to shift DKD management from a "one-size-fits-all" approach to individualized precision therapy.