Role of Lactate Dehydrogenase A (LDHA)-Mediated Glycolytic Switch in AKI

Background: Acute kidney injury (AKI) is a detrimental and frequently irreversible loss of renal function that affects millions of individuals worldwide. Despite effective biomarkers, treatment options are limited, and outcomes from AKI remain poor. Proximal tubule cells (PTCs) are among the key functional renal cell populations significantly affected by AKI. In particular, the bioenergetics of PTCs are diminished during AKI, followed by maladaptive responses accompanied by hypoxia or endotoxin-induced inflammation. In this setting, lactate dehydrogenase A (LDHA), an enzyme involved in glycolysis, is activated in PTCs, although the impact of this activation and therapeutic potential of LDHA in AKI remain to be determined. Methods: Nephron-specific LDHA knockout mice were generated by crossbreeding Pax8-rtTA/tetO Cre and LDHAfl/fl mice. Western blot, real-time PCR, and immunofluorescence analyses were used to determine LDHA levels in wild-type and LDHA-deficient mice. For an AKI model, (LDHAWhole Nephron-/-) and LDHA wild-type (LDHAWhole Nephron+/+) mice were subjected to Cisplatin (20 mg/kg; i.p., once) -induced injury. The severity of AKI, including serum creatinine levels, glomerular filtration rate (GFR), and Neutrophil gelatinase-associated lipocalin (NGAL) expression, was determined 4 days post-injection of Cisplatin. Results: Both LDHA expression and protein levels were diminished in the whole nephron of LDHA knockout mice, while LDHB remained unchanged. Control groups of (LDHAWhole Nephron-/-) mice showed no phenotype changes in proximal tubules. However, these mice developed more severe injury upon Cisplatin-induced AKI compared to wild-type counterparts. The severity of injury included increased serum creatinine levels, reduced glomerular filtration rate, and increased NGAL expression in (LDHAWhole Nephron-/-) compared to wild-type mice. Conclusion: Collectively, our findings indicate that LDHA deficiency increases the severity of Cisplatin-induced AKI, predominantly due to more significant dysfunction of proximal tubule cells. These results suggest that the accumulation of endogenous LDHA has a protective effect in AKI. Funding: NIDDK Support