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Kidney Week

Abstract: TH-PO121

Unveiling the Role of Lactate Dehydrogenase A (LDHA) in AKI: Insights from a Transgenic Mouse Model Study

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

  • Lu, Yan, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Zmijewska, Anna Alicja, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Cheung, Matthew David, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Jiang, Yanlin, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Traylor, Amie, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Osis, Gunars, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Agarwal, Anupam, The University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Acute kidney injury (AKI) is a pressing global health concern, affecting millions of individuals worldwide. Despite its high prevalence, the prognosis of AKI remains poor, and effective biomarkers, prevention strategies, and treatment options are limited. Accumulating evidence from clinical, animal, and in vitro studies supports a close association between AKI, inflammation, and metabolic dysregulation.

Notably, proximal tubule cells (PTCs) within the kidney play a vital role in AKI, as they possess numerous mitochondria with high metabolic activity, serving as both early sensors and major effectors in this condition. Additionally, under hypoxia and LPS-induced inflammation, lactate dehydrogenase A (LDHA), an enzyme involved in fermentative glycolysis, is upregulated in PTCs. However, the specific role of LDHA in AKI remains unexplored.

Methods

To generate kidney proximal tubule-specific LDHA knockout mice, we used PEPCK Cre crossbreeding with LDHA floxed mice.
To confirmed the deletion of LDHA , we use western blot and immunostaining for characterization
To induce AKI in both the LDHA knockout (KO) mice and wild-type (WT) mice, we administered a single dose of cisplatin (20mg/kg, IP)
To assess the severity of AKI, we utilized various measurements, including serum creatinine levels, survival rates, and glomerular filtration rate (GFR). GFR was evaluated by employing transdermal measurement of excretion kinetics FITC.

Results

In our preliminary study, baseline observations did not reveal any phenotype changes in LDHA KO mice within the proximal tubules. However, when subjected to cisplatin-induced AKI through a single dose injection, LDHA KO mice exhibited more severe injury compared to wild-type (WT) mice. This phenotype was confirmed by increased serum creatinine levels at day 3 post-injection in KO mice (KO: 0.689 mg/dl vs WT: 0.338 mg/dl; p=0.0062), a lower 5-day survival rate in KO mice (KO: 70% vs WT: 90%), and reduced glomerular filtration rate (GFR) in KO mice (KO: 82.6 ml/min/100g b.w. vs WT: 256.6 ml/min/100g b.w. ; p= 0.022).

Conclusion

Overall, our findings suggest that LDHA may play a significant role in exacerbating AKI may through the facilitation of glycolytic switch within the proximal tubule.

Funding

  • NIDDK Support