Research Award Recipients

Caspase-3 invalidation for protection of renal blood vessels and prevention of renal failure after transplantation

Co-applicant(s): Alice Doreille, Francis Migneault, Héloïse Cardinal

Lay Abstract

Background: When a kidney is transplanted, it is removed from the donor and temporarily deprived of blood before circulation is restored in the recipient. This process, called ischemia and reperfusion, can damage the kidney’s tiny blood vessels. Such damage often leads to scarring (fibrosis), which reduces how long the kidney will function. This problem is especially common for kidneys from older donors, which already have fewer small blood vessels and more scarring. Our team has discovered that removing a gene called caspase-3 in mice protects these tiny blood vessels, prevents scarring, and improves kidney function after injury What is not yet known is whether this gene also contributes to blood vessel loss and scarring that occur naturally with aging and whether we could protect kidneys from older individuals by inhibiting this gene. Early signs from our work suggest this might be the case. If confirmed, this could open the door to strategies aimed at better preserving kidneys from older donors, an important goal given the current shortage of organs.

Methods: We have developed a mouse model in which caspase-3 can be removed specifically from blood vessels at any time after birth. Using this model, we will: 1. Test whether removing caspase-3 throughout life prevents blood vessel loss, scarring, and kidney function decline with aging. 2. Test whether removing caspase-3 in older mice, just before they undergo ischemia and reperfusion, protects their kidneys from damage. We will monitor kidney health using standard blood tests (creatinine), microscopic analysis, advanced imaging to count blood vessels, and blood pressure measurements (since high blood pressure is linked to kidney disease). In parallel, we will analyze kidney biopsies from 191 transplant patients collected before surgery, to see if early signs of caspase-3 activation predict worse long-term transplant outcomes after kidney transplantation.

Anticipated Outcomes: We expect that blocking caspase-3 will protect kidney blood vessels, reduce scarring, and preserve kidney function in mice. In patients, we expect that signs of caspase-3 activity in pre-transplant biopsies will help predict the risk of long-term kidney failure.

Patient Engagement: We will work with the Canadian Donation and Transplantation Research Program (CDTRP) patient partners to ensure patient priorities are integrated throughout our research plan and knowledge-sharing activities.

Relevance to Patients and Community: If successful, this work could lead to new ways of protecting kidneys during transplantation, especially from older donors, ensuring they function for as long as possible. It could also lead to diagnostic tools that help predict which kidneys are at higher risk of failure, allowing better prevention and more personalized care.

Conclusion: By combining studies in animal models with research in transplant patients, this project aims to develop both preventive strategies and predictive tests to extend the life of transplanted kidneys and improve outcomes for patients living with kidney failure.