Targeting LCAD in Acute Kidney Injury

New research from the laboratories of Sunder Sims-Lucas, PhD, associate professor of Pediatrics in the Division of Pediatric Nephrology at UPMC Children's Hospital of Pittsburgh, and Eric Goetzman, PhD, professor of Pediatrics, from the Division of Genetic and Genomic Medicine, reveals possible therapeutic implications for mitigating acute kidney injury (AKI). The study, titled "Loss of long-chain acyl-CoA dehydrogenase protects against acute kidney injury," was published in JCI Insight in February 2025.  Takuto Chiba, PhD, as first author. Also collaborating on the study were researchers from the Buck Institute for Research on Aging.

This study provides new insights on the protective role that the loss of long-chain acyl-CoA dehydrogenase (LCAD) confers against AKI in two different experimental models the labs have been using in their recent AKI research. The findings point toward the identification of potential new pathways for targeted clinical interventions.

The Role of LCAD in AKI

Acute kidney injury remains a significant clinical challenge that still has no approved therapeutics to prevent, treat, or reverse it. Within the setting of AKI, the renal tubular epithelial cells (RTECs), which are highly dependent on fatty acid oxidation (FAO) for their energy needs, are particularly vulnerable to injury when normal cellular process are impaired. However, mitochondrial FAO generates hydrogen peroxide (H2O2), contributing to oxidative stress and cellular injury during AKI.

The main objective of the research was to see how alterations in LCAD, an enzyme that is important to the process of mitochondrial FAO, influence kidney damage during AKI. 

In prior related research, the team has shown that LCAD could directly generate H2O2, which could increase the severity of kidney injury. The new research expands on the prior work by evaluating the protective effects of genetically removing LCAD in two different AKI models – cisplatin-induced nephrotoxic injury and ischemia/reperfusion injury (IRI).

"We focused on understanding whether LCAD contributes to renal cellular damage through oxidative stress, and if inhibiting its action might show some kind of protection against AKI," says Dr. Sims-Lucas.

Main Findings from the Study

In both of the experimental models, the team found that when LCAD expression was genetically knocked down, the models showed substantial renal protection with less injury to the renal tubular epithelial cells. They also found less oxidative stress, and fewer biomarkers associated with kidney damage, including the presence of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1).

The research also found that cellular mitochondrial function was preserved in LCAD-deficient mice. Increased levels of mitochondrial respiration was seen in addition to an increase in the number of peroxisomes. Peroxisomes are cellular components involved in a parallel FAO pathway that can reduce the level of oxidative damage by eliminating harmful H2O2. 

"Our findings indicate that reducing LCAD activity blunts damage from mitochondrial oxidation and leads to the use of an alternative metabolic pathway to maintain energy production in kidney cells," says Dr. Sims-Lucas.

The study also investigated ferroptosis, which is a type of cell death that has been linked to oxidative stress in AKI. In the team’s experiments, both models showed fewer signs of ferroptosis, including increased levels of protective enzymes and decreased markers of oxidative stress. In essence, less oxidative damage translates to a more protective state in the kidney’s cells.

"Our study shows the potential for new therapeutic strategies that specifically target renal oxidative stress pathways without significantly impacting other vital organs," says Dr. Sims-Lucas. “Since human LCAD expression is primarily limited to the kidney, liver, lung, and pancreas, targeted inhibition may lessen the possibility of negative off-target or systemic effects compared to a broader mitochondrial inhibition approach.”

What’s Next for the Research?

Future research collaborations from the Sims-Lucas and Goetzman Laboratories include validating these findings in more targeted cell-type-specific models and exploring pharmacological options that may modulate LCAD activity therapeutically. 

"The next steps in our research involve determining how we can best translate these findings into therapeutic interventions capable of benefiting patients," says Dr. Sims-Lucas.

Study Reference

Chiba T, Oda A, Zhang Y, Pfister KE, Bons J, Bharathi SS, Kinoshita A, Zhang BB, Richert AC, Schilling B, Goetzman ES, Sims-Lucas S. Loss of Long-chain Acyl-CoA Dehydrogenase Protects Against Acute Kidney Injury. JCI Insight. 2025 Feb 11: e186073. Online ahead of Print.