Loss of Proximal Tubule Lactate Dehydrogenase A Exacerbates Nephrotoxic Acute Kidney Injury Through Metabolic Dysregulation

Acute kidney injury (AKI) involves abrupt loss of kidney function driven in part by proximal tubule metabolic stress, yet the role of glycolytic regulation in tubular injury susceptibility remains unclear. Lactate dehydrogenase A (LDHA) is a key regulator of glycolytic flux and redox balance, but its function in proximal tubules during AKI is poorly defined. In this work, we use a cisplatin-induced AKI model to investigate the role of proximal tubule LDHA in regulating metabolic responses and injury severity. Proximal tubule-specific LDHA knockout mice (PEPCKCreLDHAΔ/Δ) and LDHAflox/flox controls were subjected to cisplatin-induced AKI. Untargeted metabolomics of kidney cortex and single-nucleus RNA sequencing (snRNA-seq) were performed to define metabolic and cell-specific transcriptional responses. Loss of proximal tubular LDHA exacerbated cisplatin-induced AKI, as evidenced by worsened kidney function and tubular injury, accompanied by increased expression of inflammatory markers following injury. The analysis also showed a distinct metabolic profile at baseline in LDHA-deficient kidneys, which became more pronounced after cisplatin exposure, with coordinated changes in purine and nucleotide metabolism, energy-related metabolites, and pathways linked to redox balance and mitochondrial function. snRNA-seq revealed intrinsic transcriptional changes within proximal tubule cells at baseline and after injury, reflecting cellular stress and metabolic remodeling without strong activation of classic inflammatory gene programs. Together, these findings identify proximal tubular LDHA as a key regulator of metabolic flexibility and injury tolerance in cisplatin-induced AKI, and suggest that disrupted coordination of glycolytic and nucleotide metabolism increases tubular vulnerability, highlighting metabolic regulation as a potential therapeutic target.NEW & NOTEWORTHY This study identifies proximal tubule lactate dehydrogenase A (LDHA) as a critical regulator of metabolic flexibility during cisplatin-induced acute kidney injury (AKI). Using a tissue-specific genetic approach and integrated multi-omics, we show that loss of LDHA worsens kidney injury and inflammatory responses while disrupting metabolic adaptation in proximal tubules. These findings highlight metabolic regulation within proximal tubules as a key determinant of injury tolerance and a potential therapeutic target in AKI.