UPMC Children’s Pediatric Nephrology Researcher Rannar Airik, PhD, Receives NIH R01 to Study FAN1 in Kidney Repair and CKD Progression
November 2, 2026
Rannar Airik, PhD, associate professor of pediatrics in the Division of Pediatric Nephrology at UPMC Children’s Hospital of Pittsburgh, was awarded a National Institutes of Health R01 grant that will continue the laboratory’s research into why renal tubular epithelial cells fail to recover after acute kidney injury (AKI) and how that failure drives progression to chronic kidney disease (CKD).
The Airik Laboratory's current research is focused on FAN1, which is a DNA repair enzyme, the loss of which impairs the ability of injured renal tubular epithelial cells, and specifically those of the proximal tubule, to recover after an AKI. The new R01 grant will help propel Dr. Airik's research from defining the mechanistic processes to testing if FAN1 can be manipulated to prevent or reverse CKD progression.
"This grant lets us build directly on our preliminary data," Dr. Airik says. "The question we are trying to answer is if restoring FAN1, or protecting the functions it normally performs, can slow or stop the progression from kidney injury to chronic disease."
The Role of FAN1 Loss in Inherited and Acquired CKD
Dr. Airik first studied FAN1 in the context of a rare inherited kidney disease (karyomegalic interstitial nephritis (KIN) caused by mutations in the gene. In the nucleus, FAN1 repairs DNA damage in tubular cells. When FAN1 function is lost, that damage continues and DNA damage signaling remains active. The result of this process leads to progressive fibrosis and kidney injury.
KIN only develops when both copies of the FAN1 gene are mutated. The lab's preliminary work in animal models has shown that losing even one copy makes the kidney more susceptible to injury. Establishing that susceptibility is one of the first goals of the new work.
"The practical implication of this finding means that a person who carries one mutated copy of FAN1 could be more vulnerable to environmental factors affecting the kidneys or to nephrotoxins and other kidney injury that could result in a clinical setting, such as happens with certain chemotherapy agents used to treat cancer," Dr. Airik says. "This has not been recognized previously."
Dr. Airik’s lab has used cisplatin to induce kidney injury in its experimental models. That approach gained a clinical counterpart when Dr. Airik and his team identified a patient with a FAN1 mutation who developed kidney injury after receiving low-dose cisplatin. The case supports the lab’s hypothesis that FAN1 deficiency leaves the kidney more vulnerable to injury from nephrotoxic agents.
Restoring FAN1 After Kidney Disease Has Set In
In the lab's preclinical models, increasing FAN1 expression in the renal tubular epithelial cells protected the kidney from cisplatin injury. The open question around that finding is if restoring FAN1 still offers a protective effect once CKD has developed, or if by that point it is too late. Dr. Airik and the team will test this by delivering a functional copy of FAN1 to the renal tubular epithelial cells of the models using adeno-associated viral vectors (AAV) after kidney disease has been established. This approach depends on getting the copy of the gene into the right cells in the kidney.
"Adeno-associated viruses have been notoriously poor at targeting kidney tubular cells because the viral serotypes do not interact with the right receptors," Dr. Airik says. "Newer serotypes have been developed, and in our studies so far they work well. We are now able to target kidney tubular cells with an AAV-mediated approach, which was not possible before."
The gene therapy work is being conducted in collaboration with the Gittes Laboratory for Diabetes and Pancreatitis Research at UPMC Children’s, which is directed George Gittes, MD, the Benjamin R. Fisher Chair of Pediatric Surgery, scientific co-director of research at UPMC Children’s, and director of the Richard King Mellon Foundation Institute for Pediatric Research. Dr. Gittes’ research lab focuses on restoring insulin production in pancreatic beta cells.
Protecting the Tubular Cells Mitochondria When FAN1 Function is Lost
FAN1 also has a role outside the nucleus of the cell. Dr. Airik’s lab has found that FAN1 also localizes to mitochondria and that its loss impairs mitochondrial respiration, increases the production of reactive oxygen species, and leads to an accumulation of damaged mitochondria. Dr. Airik and his team will determine whether FAN1 is required to maintain mitochondrial DNA, which mitochondria depend on to produce energy.
"We think some of the kidney damage stemming from FAN1 deficiency comes from the mitochondria," Dr. Airik says. "Without FAN1, they may not be able to produce enough energy or carry out fatty acid oxidation properly. That would be a function of FAN1 that has yet to studied definitively."
The mitochondrial findings are the basis for the lab's work with JP4-039, a mitochondria-targeted antioxidant developed in the laboratory of Peter Wipf, PhD, Distinguished University Professor in the Department of Chemistry at the University of Pittsburgh. JP4-039 accumulates in mitochondria and neutralizes the reactive oxygen species that build up there after injury. Dr. Airik’s lab has tested JP4-039 in preclinical models of cisplatin-induced AKI, where the treatment reduced oxidative stress within mitochondria, preserved mitochondrial integrity, and improved both kidney function and the histologic injury to the tubular cells. Those data show that limiting mitochondrial injury can change the course of kidney damage after an acute injury. Dr. Airik and his team will now test JP4-039 to see if it can suppress oxidative stress in FAN1-deficient cells and protect the mitochondrial DNA that FAN1 would otherwise maintain.
Testing the Findings in Human Kidney Tissues
Dr. Airik and his team also are studying FAN1 in human kidney organoids, in collaboration with Neil Hukriede, PhD, professor in the Department of Cell Biology at the University of Pittsburgh who has developed vascularized kidney organoids as part of his lab’s work on AKI, the mechanisms of kidney regeneration, and identifying agents that can increase the number of renal progenitor cells. Including studies in human tissue derived organoids is consistent with the NIH’s recent push to incorporate more human-based tissues, such as organoids wherever possible into research projects.
"Organoids let us study FAN1 in human kidney cells instead of relying only on animal models, and we expect them to let us test JP4-039 faster," Dr. Airik says. "Dr. Hukriede's organoids are useful because they include blood vessels alongside the tubular cells, as an actual kidney does. They still have no blood flow or connection to the glomeruli, but the cells develop into the different segments of the nephron and function as they should."
References and Further Reading
Targeting DNA Damage and Mitochondrial Dysfunction in Chronic Kidney Disease. Project Number: R01DK148060.
Zhou W, Otto EA, Cluckey A, Airik R, et al. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat Genet. 2012; 44(8): 910-915.
Airik R, Schueler M, Airik M, et al. A FANCD2/FANCI-associated nuclease 1-knockout model develops karyomegalic interstitial nephritis. J Am Soc Nephrol. 2016; 27(12): 3552-3559.
Airik M, Phua YL, Huynh AB, et al. Persistent DNA damage underlies tubular cell polyploidization and progression to chronic kidney disease in kidneys deficient in the DNA repair protein FAN1. Kidney Int. 2022; 105(5): 1042-1056.
Airik M, Arbore H, Childs E, et al. Mitochondrial ROS triggers KIN pathogenesis in FAN1-deficient kidneys. Antioxidants (Basel). 2023; 12(4): 900.
Airik M, Clayton K, Wipf P, Airik R. JP4-039 mitigates cisplatin-induced acute kidney injury by inhibiting oxidative stress and blocking apoptosis and ferroptosis in mice. Antioxidants (Basel). 2024; 13(12): 1534.
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