Kidney Week

Abstract: SA-PO0137

Renal Epithelial Lactate Dehydrogenase A Is Essential for Ischemic AKI

Session Information

• AKI: Mechanisms - 3
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Reeves, William Brian, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

William Brian Reeves, MD, FASN

• Wang, Weiwei, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Weiwei Wang, MS

• Li, Kang, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Kang Li, PhD

Background

We previously determined that inhibition of Lactate Dehydrogenase (LDH) using small molecule inhibitors prevented ischemic and cisplatin-induced AKI. We also found that treatment of mice with exogenous lactate worsened ischemic and cisplatin-induced AKI and overcame the protective effects of LDH inhibitors, suggesting that LDH mediates AKI through the production of lactate. The LDH inhibitors act systemically and inhibit both the LDHA and LDHB isoforms. LDHA mediates the conversion of pyruvate to lactate while LDHB mediates the conversion of lactate to pyruvate. Here, we investigated the isoform and tissue specificity of LDH which mediates ischemic AKI.

Methods

We bred mice expressing cre recombinase under the control of the Pax8 promoter (Pax8-cre) with mice in which Exon 3 of the LDHA gene is flanked by LoxP sites (LDHA^FL/FL) to create Pax8-cre LDHA^FL/FL mice.

Results

Western blot analysis of the kidneys from WT and LDHA^FL/FL and Pax8-cre mice showed abundant expression of LDHA. In contrast, LDHA expression was almost completely absent in Pax8-cre LDHA^FL/FL mice. Likewise, immuno-staining for LDHA revealed mainly proximal tubule expression in WT and LDHA^FL/FL mice but no staining in Pax8-cre LDHA^FL/FL mice, confirming deletion of LDHA in tubular epithelial cells. LDHA^FL/FL and Pax8-cre LDHA^FL/FL mice were subjected to 26 minutes of ischemic injury. As shown in the Figure, LDHA^FL/FL mice developed severe AKI while Pax8-cre LDHA^FL/FL did not. Histologic injury and inflammation were also dramatically reduced in the Pax8-cre LDHA^FL/FL mice.

Conclusion

These results: confirm the important role of LDH in ischemic AKI; indicate that the LDHA isoform is critical for AKI, and; indicate that expression of LDHA, and the production of lactate, within renal epithelial cells is critical for, at least ischemic, AKI. Further studies are needed to determine if renal LDH expression and lactate production underlie other forms of AKI. Inhibition of LDH may be an effective strategy to prevent AKI.

BUN and creatinine levels at baseline and 24 hr after IRI in LDHA^FL/FL and Pax8-cre LDHA^FL/FL mice.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025karegd2a