Kidney Week

Abstract: SA-PO131

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

Session Information

• AKI: Metabolism and Cell Death
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Lu, Yan, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Yan Lu, MD

• Zmijewska, Anna Alicja, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Anna Alicja Zmijewska, MS

• Agarwal, Anupam, The University of Alabama at Birmingham, Birmingham, Alabama, United States

Anupam Agarwal, MD, FASN

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, (LDHA^{Whole Nephron-/-}) and LDHA wild-type (LDHA^{Whole 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 (LDHA^{Whole 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 (LDHA^{Whole 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