UPMC Children’s Pediatric Nephrologist, Aidan Porter, MD, Awarded NIH K08 Grant to Study Unfolded Protein Response in Acute Kidney Injury
September 12, 2024
Aidan Porter, MD, from the Division of Pediatric Nephrology at UPMC Children's Hospital of Pittsburgh, has been awarded a National Institutes of Health (NIH) K08 grant to support his basic science research on molecular and cellular mechanisms of acute kidney injury (AKI).
Acute Kidney Injury: Prevalent With a Continuing Lack of Therapeutic Options
AKI affects a substantial number of hospitalized patients, including up to 65% of those in intensive care units. In children, the causes of AKI can vary widely, from heart failure to nephrotoxic medications such as chemotherapeutics, to sepsis. Treatment options for AKI remain limited, typically involving supportive care, such as optimizing fluid management and, in the most severe cases, dialysis. There are no specific therapies available to prevent or reverse AKI.
“We need targeted therapies for AKI, plain and simple,” says Dr. Porter. “Kidneys do not regenerate well, so any injury can have long-lasting consequences, particularly for children. My goal with this research is to better understand the mechanisms that drive kidney injury, which could eventually inform new treatment strategies.”
K08 Grant and Research Focus
Dr. Porter’s research centers on the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the progression of AKI. The ER is responsible for maintaining protein balance in cells. When this balance is disrupted, the UPR is activated. This pathway helps protect cells in the short term but may lead to cell death if the stress persists. Dr. Porter’s K08 research project aims to understand how the UPR contributes to kidney injury and whether targeting this pathway could mitigate downstream damage.
“The UPR is a cellular response mechanism that can transiently protect cells from stress, but when stress is too severe or prolonged, the UPR can cause cell death,” says Dr. Porter. “In the context of AKI, where kidney cells are already vulnerable, that shift can be particularly damaging.”
To study the process, Dr. Porter and his collaborators have developed a mouse model in which the ER protein GRP170, a regulator of protein homeostasis, can be selectively deleted. This model allows Dr. Porter to study how disruptions in ER function contribute to the formation and persistence of AKI. Early data from his research suggest that one particular UPR sensor, PERK, likely plays a central role in mediating the switch from cellular protection to cell death during AKI.
The project’s first objective is to define how PERK contributes to AKI using two clinically relevant models: one involving the nephrotoxic chemotherapy drug cisplatin, and another focused on ischemia-reperfusion injury (IRI).
“Cisplatin is a well-known cause of nephrotoxicity, and it provides a good model for understanding the nephrotoxic pathway in AKI,” says Dr. Porter. “We’re also looking at ischemia-reperfusion injury, which occurs in conditions such as congenital heart disease or after surgeries that temporarily impair kidney blood flow.”
Therapeutic Implications and Future Directions
A primary goal of Dr. Porter’s research is to explore whether PERK inhibitors can prevent the harmful effects of UPR activation during AKI. Although current PERK inhibitors are not suitable for clinical use due to off-target effects, they can provide valuable insights into the mechanisms driving AKI and possibly help identify more specific targets downstream of PERK that could lead to safer therapeutic options.
“While existing PERK inhibitors have toxicity issues, they’re useful in helping us understand the underlying pathways involved in AKI,” says Dr. Porter. “The long-term goal is to find more specific PERK modulators that can block the harmful effects of UPR activation without causing additional damage.”
In the future, Dr. Porter plans to expand his research to study other cellular stress pathways that may contribute to kidney disease. This broader focus will include stress sensors in the cytoplasm and other organelles, which may also play a role in regulating kidney cell health.
“I expect my research will continue to investigate how other stress pathways influence kidney injury,” says Dr. Porter. “Understanding these mechanisms will be key to developing targeted therapies that could intervene early and potentially prevent AKI from progressing.”
Dr. Porter’s research is supported by mentors, including Jeffrey Brodsky, PhD, who is the Avinoff Professor of Biological Sciences at the University of Pittsburgh, and division colleague Sunder Sims-Lucas, PhD, associate professor of Pediatrics.
“I think this research holds promise for filling the gap in available treatments for pediatric AKI, potentially offering new ways to protect kidney function and improve outcomes for patients,” says Dr. Porter.
Reference and Further Reading
Prior Articles from UPMC Physician Resources on Dr. Porter’s Research
