Mitoprotective therapies for kidney injury

University Of Tennessee Health Sci Ctr, Memphis TN

Investigators

Abstract

ABSTRACT Acute kidney injury (AKI) is a common disease that is associated with adverse short and long-term sequelae. AKI usually occurs in hospitalized patients and in the settings of other clinical conditions, such as sepsis, rhabdomyolysis, and cardiovascular and oncological diseases, where the underlying disease and or associated therapeutic intervention causes abrupt loss of renal function. While the causal mechanisms are incompletely understood, renal tubular epithelial cell (RTEC) dysfunction and cell death is the pathological lesion that initiates and triggers AKI. Importantly, it has now been established that disruption of mitochondrial homeostasis in the early stages of acute kidney injury drives subsequent RTEC cell death and AKI. Pharmacological interventions that stabilize mitochondrial function could thus mitigate AKI and or augment recovery, however, mitochondria- localized druggable targets have remained elusive. Utilizing unbiased functional genomic and chemical genetic screens, here, we have identified a mitochondria-localized druggable protein Phospholipid Scramblase 3 (PLSCR3) as a biological target of mitoprotective tetra-peptide drug SS-31. Our preliminary studies using complementary pharmacological and genetic approaches demonstrate that activation of PLSCR3 stabilizes mitochondrial function, reduces RTEC cell death, and mitigates AKI. Furthermore, we have identified novel orally bio-available small-molecule activators of this mitochondrial protein. In the current application, we propose to utilize genetic, biochemical, cell biology, pharmacokinetics, and pharmacological approaches to characterize this novel activator. We hypothesize that pharmacological augmentation of PLSCR3 function through a novel agonist (AB-3) or transcriptional upregulation (Belumosudil, an FDA-approved ROCK2 kinase inhibitor) would alleviate mitochondrial dysfunction, TEC death, and AKI. To test our hypothesis and accomplish the objective of developing new mitochondrial-targeted AKI therapeutics, we plan to: (a) Determine target specificity, pharmacological properties, in vivo pharmacokinetics of AB-3 and Belumosudil in mice and pigs and (b) Determine the efficacy of AB-3 and Belumosudil in ischemia-reperfusion (I/R), cisplatin nephrotoxicity, and rhabdomyolysis associated murine models of AKI along with I/R porcine model of AKI. The proposed research is highly significant because, at the end of the project, we expect to identify a small molecule activator with a defined mechanism of action and novel mitochondrial stabilizing activity. Our proposed studies will provide compelling proof-of-principle data reinforcing the groundwork for the development and subsequent assessment of two classes of pharmacological compounds that either activate (AB-3) or upregulate (Belumosudil) PLSCR3 as a therapeutic approach for mitigating AKI.