Cardiovascular disease accounts for over 50% of deaths in patients with end-stage kidney disease (ESKD). Renal transplantation is the preferred treatment for ESKD patients, but the shortage of transplantable kidneys results in 7 out of 10 ESKD patients having to remain on dialysis, thus increasing cardiovascular associated complication and death. Increasing viability of kidneys during extended cold storage would increase transplant availability and improve renal outcome. Unfortunately, clinical and experimental data show that the ESKD patients receiving kidneys with prolonged cold storage display poor renal outcome after transplantation. Sadly, extended cold storage-related pathways resulting in poor renal outcome is not understood. Our long-term goal is to identify the cold storage-related pathways and to adopt targeted therapies during cold storage, thereby improving transplant outcome and decreasing ESKD-associated cardiovascular death. Proposed application will investigate a hypothesis that the cold storage-mediated ROS activates the immunoproteasome (iproteasome) within kidneys to degrade Hsc70 protein, leading to renal damage after transplantation. The goal of this award is to test our hypothesis by blunting ROS or inhibiting iproteasome function (genomic and pharmacologic approach) during renal cold storage in an attempt to prevent Hsc70 protein loss and mitigate renal damage following transplantation. We propose three specific aims, using a rat renal transplant model, to test our hypothesis: Aim 1: Evaluate the effects of MitoTEMPO on the iproteasome and renal function following cold-storage plus transplantation. Aim 2: Identify mechanisms responsible for the loss of Hsc70 protein during cold-storage plus transplantation. Aim 3: Assess the therapeutic effects of the selective iproteasome inhibitor ONX 0914 to improve renal outcome following cold-storage plus transplantation. Our proposed studies will establish the ROS-iproteasome-Hsc70 axis as a novel therapeutic target during cold-storage plus transplantation. If adding ONX 0914 and MitoTEMPO in the cold storage solution enhances the viability of kidneys and improves transplant outcomes in rats, these compounds will be recognized for their potential clinical application to improve kidney viability and availability and to improve transplant outcomes, thus reducing dialysis and increased susceptibility to cardiovascular disease - the leading cause of death for patients with ESKD.
|Program type||Transformational Project Award|
|Effective start/end date||07/01/2019 → 06/30/2022|