Lactate Metabolism Dysregulation Drives the Pathogenesis of Acute Kidney Injury

Acute kidney injury (AKI) remains a condition with limited effective therapeutic options, partly due to challenges in early diagnosis and timely intervention. While lactate accumulation is a hallmark of ischemic and septic AKI, the underlying mechanisms remain unclear.

This study integrated single-cell RNA sequencing data from AKI patients (GEO database) with lactate metabolism-related genes (LMRGs) to identify key therapeutic targets.

Collecting duct (CD) cells exhibited the highest LMRG expression. Machine learning algorithms and validation in bilateral ischemia/reperfusion injury (bIRI) and lipopolysaccharide (LPS)-induced AKI mouse models, as well as hypoxia/reoxygenation (H/R)-stimulated renal cells, identified Ldhb as a core gene. Disruption of lactate metabolism via BAY876 (selective GLUT1 inhibitor) or siRNA-mediated Ldhb knockdown significantly attenuated kidney injury, reduced inflammatory cytokines (IL-1β, IL-6, TNF-α), and decreased reactive oxygen species in vitro and in vivo.

These findings reveal that lactate metabolism is reprogrammed in AKI, particularly in CD cells, and identify LDHB as a novel potential therapeutic target for this condition, though further mechanistic studies are required to establish causality.