Kidney Week

Abstract: FR-PO0341

Metabolic Pathways as Therapeutic Targets in Sepsis-Induced AKI

Session Information

• AKI: Mechanisms - Metabolism and Repair
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Hyatt, Dylan Michael, University of California San Diego, La Jolla, California, United States

Dylan Michael Hyatt, MD, MS

• Singh, Prabhleen (Sheena), University of California San Diego, La Jolla, California, United States

Prabhleen (Sheena) Singh, MD, MPH

Background

In the cecal ligation and puncture (CLP) model of sAKI, we showed reduced oxidative metabolism, increased glycolytic enzymes, but decreased functional glycolysis. Here, we focus on pyruvate dehydrogenase (PDH) and its inhibition by pyruvate dehydrogenase kinase (PDK) and Sirtuin3 (Sirt3), which can activate PDH as a key regulatory point between oxidative (OXPHOS) and glycolytic metabolism(Panel1) in the response to sAKI.

Methods

Glucose and pyruvate metabolic pathways were examined by assessing protein and mRNA expression of key components, PDH-PDK axis and regulation by Sirt 3 in kidneys from sham, CLP, WT and PDK4^-/- mice . Metabolic assessment in proximal tubule (PTs) with Agilent Seahorse assay, RNA sequencing and metabolomics were performed for a comprehensive assessment of renal metabolism in sAKI.

Results

Glucose transporters(panel2A), and gluconeogenic enzymes(panel2B) were decreased, and pentose phosphate pathway (PPP) enzymes were increased in CLP(panel2C). ATP-linked and maximal respiration were reduced with pyruvate oxidation inhibition vs. fatty acid oxidation inhibition in CLP PTs(Panel3). PDH subunits were reduced and phospho-PHD was increased in CLP(Panel4A). PDK4 was increased, while pyruvate dehydrogenase phosphatase2 (PDP2), which activates PDH (Panel4B-C) and Sirt3, which regulates PDH activation, was reduced in CLP (Panel5). In PDK4^-/- mice, PDHE3, PDP2 and Sirt3 were increased(Panel6). Pre- and post-CLP GFRs showed a greater decrease in WT vs. PDK4^-/- mice (308±4 vs. 248±8 ul/min, p=0.002), showing mitigation of sAKI. Targeted transcriptomic and metabolomic analyses showed metabolic alterations consistent with these results in CLP kidneys (Panel7).

Conclusion

We show strong evidence for PDH-PDK and Sirt3 interaction in sAKI with upregulation of glycolytic and PPP enzymes with impaired downstream functional glycolysis and ATP generation. Inactivation of PDH by increased PDK4 and low Sirt3, likely diverts pyruvate away from OXPHOS increasing susceptibility to sAKI. (Panel8). Both PDK and Sirt3 are clinically relevant therapeutic targets in mitigating injury and enhancing recovery in sAKI.

Funding

• NIDDK Support