Kidney Week

Abstract: TH-PO122

Lactate Dehydrogenase (LDH): Not Just a Marker of Kidney Injury

Session Information

• AKI: Mechanisms - I
  November 02, 2023 | Location: Exhibit Hall, Pennsylvania 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, San Antonio, Texas, United States

William Brian Reeves,

• Wang, Weiwei, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Weiwei Wang,

• Li, Kang, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Kang Li,

• Madesh, Muniswamy, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

Muniswamy Madesh,

Background

Lactate dehydrogenase (LDH) catalyzes the final step in glycolysis, the conversion of pyruvate to lactate. The release of LDH into extracellular fluids has been used for decades as a clinical and experimental marker of cell injury. However, the role of LDH as a mediator of cell injury has not been examined. Glycolysis is increased in AKI leading to the accumulation of lactate. Here we show that LDH and lactate are, in fact, not just markers but potent mediators of AKI.

Methods

C57BL6 male mice were subjected to bilateral ischemia reperfusion injury (IRI). Mice received LDH inhibitors (oxamate 300 mg/kg or NCATS SM1441 10 mg/kg), lactate (2g/kg), the Mrs2 inhibitor CPACC (10 mg/kg/d) or vehicle. Renal function and structure were assessed 24 hr after reperfusion.

Results

Oxamate-treated mice developed substantially less structural damage and kidney dysfunction (BUN 38±7 mg/dl, Cr 0.37±0.06 mg/dl) than vehicle-treated mice (BUN 148±25, Cr 0.93±0.12, P<0.0001). NCATS SM1441 also prevented ischemic AKI (NCATS BUN 31±6, Cr 0.23±0.06 vs saline BUN 111±10, Cr 1.59±0.3, P<0.0001). Administration of NCATS up to 6 hours after reperfusion also reduced IRI. LDH inhibitors also reduced hypoxic and cisplatin-induced cell death in renal epithelial cells in vitro. Moreover, the administration of L-lactate (but not D-Lactate) sensitized mice to a subsequent mild (22 min) ischemic insult (BUN L-lactate 95±8 vs D-lactate 22±6, P<0.0001) and also abrogated the protective effects of LDH inhibitors. In prior work, we showed that lactate stimulates mitochondrial Mg²⁺ uptake via Mrs2 and that Mrs2 mediates ischemic AKI. Here, we found that lactate did not exacerbate AKI in the absence of Mrs2. Finally, inhibition of LDH or Mrs2 starting 3 days after IRI, when injury is established, preserved kidney function and reduced fibrosis and atrophy measured at day 28.

Conclusion

These results indicate that the production of lactate via LDH is an important mediator of ischemic AKI and support the view that lactate-triggered mitochondrial Mg²⁺ uptake mediates AKI. These results also support the view that a sustained increase in glycolysis contributes mechanistically to the AKI-CKD transition. Finally, we provide preclinical evidence that LDH inhibitors may be highly effective in preventing ischemic AKI when administered before or shortly after injury and in preventing the development of CKD when administered after AKI.