Dissertation/Thesis Abstract

The Mitochondrial BK Channel as a Novel Therapeutic Target During Renal Cold Storage and Transplantation: Its Role as a Mitochondrial-Protective Factor
by Shrum, Stephen A., Ph.D., University of Arkansas for Medical Sciences, 2020, 205; 28094241
Abstract (Summary)

Last year ~34% of donor kidneys were discarded due in part to injury that occurs during cold storage (CS), leading to a high mortality of patients waiting for transplantation. Deceased donor kidneys exposed to CS are five-fold more likely to fail than those from living donors (without CS). Thus, there is a critical need to investigate mechanisms involved with CS-induced renal injury, which will help advance the development of novel therapeutic interventions to improve transplant outcomes.

Our laboratory and others have shown that CS ‘alone’ induces renal mitochondrial dysfunction and oxidative injury. However, the extent of injury when CS is combined with transplantation (CS+Tx) as well as the identity of specific mitochondrial targets remain elusive. Exploring these questions was the primary goal of this dissertation project. First, using a novel rat renal transplant model, we demonstrated that even short-term (4h) CS exacerbates mitochondrial and renal injury after Tx compared to Tx alone (without CS). Next, we speculated that the mitochondrial large-conductance Ca2+-activated K+ channel (mitoBK) was a potential therapeutic target since its activation has been shown to be mitochondrial-protective during warm ischemic injury. The hypothesis to be tested is CS-induced mitochondrial ROS impair mitoBK channel function, which contributes to renal and mitochondrial injury. Addition of BK activators during CS protects against mitochondrial and renal injury following transplantation.

Using our rat renal cell line (NRK), we identified, for the first time, the presence of an active mitoBK channel. Cells exposed to CS followed by rewarming (CS+RW) significantly reduced mitoBK function. Excitingly, addition of the specific BK activator, NS11021 (1 μM), during CS restored mitoBK function and mitigated CS+RW-induced mitochondrial and cell injury. Finally, using our preclinical rat model of CS+Tx, NS11021 (3 μM) partially mitigated mitochondrial dysfunction and cell injury, but not renal dysfunction. Overall, these studies support our hypothesis and identify the mitoBK channel as a promising pharmacotherapeutic target for preventing CS-induced mitochondrial injury and renal injury. Future studies are warranted to better characterize mitoBK’s mitochondrial-protective role and to optimize this therapeutic approach, which is a clinically attractive strategy that avoids systemic drug exposure in the transplant recipient.

Indexing (document details)
Advisor: MacMillan-Crow, Lee Ann, Rusch, Nancy J.
Commitee: Mayeux, Philip R., Aykin-Burns, Nukhet, England, Sarah K.
School: University of Arkansas for Medical Sciences
Department: Interdisciplinary Biomedical Sciences
School Location: United States -- Arkansas
Source: DAI-B 82/4(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Pharmacology, Cellular biology, Pathology
Keywords: Cold storage, Kidney, MitoBK channel, Mitochondria, NS11021, Transplantation
Publication Number: 28094241
ISBN: 9798678181886
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