Renal Epithelial Lactate Dehydrogenase A Is Essential for Ischemic AKI

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