Advancing Mechanistic and Translational Research in Pediatric Kidney Disease – Updates from the Airik Laboratory at UPMC Children’s

Rannar Airik, PhD, leads a research program in the Division of Pediatric Nephrology at UPMC Children’s Hospital of Pittsburgh focused on the cellular and molecular mechanisms that drive kidney injury and cellular repair. The Airik Laboratory’s work is focused on how renal tubular epithelial cells respond to stress and why, in many cases, these cells fail to recover after an acute kidney injury (AKI), driving progression to chronic kidney disease (CKD).

Dr. Airik’s lab was also the recent recipient of an anonymous philanthropic donation through the UPMC Children’s Hospital Foundation to support the lab’s efforts to advance its ongoing studies and explore emerging therapeutic directions.

“The flexibility provided by philanthropic support allows us to pursue mechanistic questions and translational directions in parallel, which is difficult to achieve through more traditional funding mechanisms alone,” Dr. Airik says. “We are incredibly grateful for the support that will help further our lab’s studies.”

FAN1 and Tubular Repair in Chronic Kidney Disease

At the core of the Airik Lab’s work is the study of FAN1, a DNA repair nuclease originally identified in the context of rare genetic kidney disease. Early work established that loss of FAN1 function impairs the ability of tubular cells to repair DNA damage, resulting in progressive fibrosis and injury. More recent studies have demonstrated that FAN1 expression is downregulated in more common forms of chronic kidney disease. The lab’s work have shown that FAN1 levels decline as disease progresses. This suggests that loss of its cytoprotective function is not limited to genetic deficiency. It is also a feature of acquired kidney injury.

These findings have reframed FAN1 as a broader regulator of tubular cell health. CKD is increasingly recognized as a disorder of failed cellular repair, in which tubular epithelial cells are unable to recover from acute injury and instead adopt a maladaptive phenotype characterized by persistent inflammation, fibrosis, and loss of function. FAN1 activity contributes to sustained DNA damage signaling and impaired recovery. The Airik Lab’s work has focused on defining how this loss of function alters cellular behavior and whether restoring FAN1 activity can improve outcomes following injury.

“This has been one of the more important developments in our work. We initially studied FAN1 in the context of a rare genetic kidney disease, but what we are now seeing is that its expression is broadly reduced across different forms of CKD. That suggests it is not only causative in rare cases, but also part of the general disease process,” Dr. Airik says.

Expanding the Mechanistic Framework: FAN1 and Mitochondrial Function

An area of recent investigation has expanded the role of FAN1 beyond itsf function in nuclear DNA repair. Studies have demonstrated that FAN1 is also involved in mitochondrial biology, with evidence showing localization of the protein to the mitochondrial compartment following injury. This observation has led to a new line of inquiry into how FAN1 influences mitochondrial integrity and function in tubular cells. Loss of FAN1 is associated with impaired mitochondrial respiration, increased reactive oxygen species generation, and accumulation of damaged mitochondria.

These findings position FAN1 at the intersection of genomic stability and cellular metabolism. By linking DNA repair mechanisms to mitochondrial homeostasis, the lab’s work provides a more integrated view of how tubular cells respond to injury and why recovery fails in the setting of chronic disease. Ongoing studies are focused on defining the specific role of FAN1 within mitochondria, including its potential involvement in mitochondrial DNA maintenance and oxidative stress.

“The mitochondrial findings were not something we anticipated at the outset. We observed a clear defect in mitochondrial function in the absence of FAN1, and that led us to investigate whether the protein itself is involved in maintaining mitochondrial integrity. That has now become a central part of the project,” Dr. Airik says.

Preclinical Evidence Supporting FAN1 as a Therapeutic Target

Preclinical models have provided further support for the therapeutic relevance of this pathway. In model systems, increasing FAN1 expression in tubular cells confers protection against injury, improving both structural and functional outcomes following exposure to nephrotoxic stressors such as cisplatin. These models also demonstrate preservation of mitochondrial function, reinforcing the connection between FAN1 activity and cellular energetics.

“The consistency of the protective effect across our models has been important. It suggests that maintaining FAN1 activity is not only mechanistically relevant, but also potentially actionable from a therapeutic standpoint,” Dr. Airik says.

Targeting Mitochondrial Injury: JP4-039 and Ferroptosis

Translating these mechanistic insights into therapeutic approaches has become a central focus of the lab’s work. One of the most advanced areas of investigation involves the use of JP4-039, a mitochondria-targeted small molecule designed to reduce oxidative stress within cells. Developed by Peter Wipf, PhD, Distinguished University Professor, Department of Chemistry, University of Pittsburgh, the compound directly addresses the mitochondrial dysfunction observed in models of kidney injury.

In preclinical studies, JP4-039 has demonstrated the ability to preserve mitochondrial integrity and reduce tubular cell injury following acute insult. Treatment with the compound reduces the accumulation of reactive oxygen species within mitochondria and improves markers of kidney function and histologic injury.

“We had been using cisplatin to induce kidney injury in our experimental models, but there was no clear clinical correlate initially. When we identified a patient with a FAN1 mutation who developed kidney injury after low-dose cisplatin, it provided direct clinical support for what we were observing experimentally and reinforced the relevance of these pathways,” Dr. Airik says.

This work provides direct evidence that targeting mitochondrial injury pathways can alter the course of kidney damage. It also reinforces the broader mechanistic model emerging from the lab’s studies, in which mitochondrial dysfunction links DNA damage, metabolic stress, and cell death.

Gene Therapy Approaches to Restoring FAN1 Function

In parallel, the lab is pursuing gene-based strategies to address upstream drivers of injury, particularly the loss or suppression of FAN1. Using adeno-associated viral vectors engineered to target renal tubular epithelial cells, these studies aim to restore FAN1 expression in the kidney and evaluate its impact on injury and repair. Collaborative efforts have focused on the development of viral capsids with enhanced specificity for tubular cells, improving the feasibility of targeted gene delivery.

“The challenge with gene delivery in the kidney has always been achieving sufficient specificity for tubular cells. Advances in vector design are beginning to make that more feasible, which opens the door to testing whether restoring FAN1 expression can modify disease progression,” Dr. Airik says.

Current Direction of the Lab’s Work

Pharmacologic interventions such as JP4-039 target downstream consequences of injury, including mitochondrial dysfunction and oxidative stress, while gene therapy aims to restore upstream regulatory mechanisms involved in DNA repair and cellular homeostasis. Both approaches share an objective of preserving tubular cell function and promoting recovery following AKI.

The Airik Lab’s current work is focused on advancing these strategies in preclinical systems while continuing to refine the biology of FAN1 and its role in mitochondrial function. By integrating mechanistic studies with therapeutic development, Dr. Airik’s research is working toward interventions to alter the trajectory of kidney disease at an early stage, with the goal of preventing progression from AKI to CKD.

“The goal is to move beyond describing mechanisms and begin testing whether these pathways can be manipulated in ways that preserve kidney function,” Dr. Airik says.

Learn more about the Airik Lab.