Date of Award

5-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmaceutics

Research Advisor

Frank Park, Ph.D.

Committee

Adebowale Adebiyi, Ph.D. Santosh Kumar, Ph.D. Kafait U. Malik, Ph.D. Bob M. Moore, Ph.D. Charles R. Yates, Ph.D.

Abstract

Acute kidney injury (AKI) is a major problem clinically affecting up to two-thirds of intensive care unit patients, and results in increased hospitalization time, the risk of developing chronic kidney disease, and mortality. Hallmarks of AKI include tubular cell death and a decrease in renal perfusion which leads to decreases in renal function following injury. For 20 years the pathophysiology of AKI has been well established. However, therapies for AKI have shown minimal to no success clinically. The work here describes our efforts to further categorize the effects of CB2 activation, a possible novel therapeutic target in AKI.

There is increasing importance associated with the understanding of the biological activity of the cannabinoid receptors following the increased acceptance in the medicinal purposes of cannabis and cannabis-related compounds. The endocannabinoid system is comprised of its cognate G-protein coupled receptors, cannabinoid type 1 and 2 receptors, endogenous lipid signaling molecules, N-arachidonoyl ethanolamine (AEA) and 2-acylglycerol, and the enzymes involved in their biosynthesis and catabolism. In the kidney, the CB1 receptors consistently demonstrate deleterious effects on glomerular and tubular function in various acute and chronic forms of injury, while CB2 receptors have demonstrated the opposite effects.

This work will demonstrate the findings of studies that focus on the role of CB2 in the recovery from ischemia/reperfusion injury (IRI) and the effects of CB2 activation on both tubular cell death and renal hemodynamics. To study the effect of CB2 activation on renal damage following IRI, our scientific group tested a small molecule agonist, SMM-295 [3′-methyl-4-(2-(thiophen-2-yl) propan-2-yl) biphenyl-2,6-diol], in an investigation of the CB2 receptor as a potential therapeutic target in the prevention of tubular epithelial cell damage after AKI. To test this compound in AKI, we used a mouse model of renal bilateral ischemia-reperfusion injury (IRI), which is a common experimental model to study AKI, demonstrating considerable beneficial effects of SMM-295 following injury. Subsequently, we then investigated the possible mechanisms that undermine the effects of SMM-295, including initiation of antiapoptotic signaling cascades in tubular epithelium as well as increases in renal perfusion through a vascular effect demonstrating a multifunctional role for SMM-295 in the treatment of IRI.

Our findings demonstrate that CB2 activation by SMM-295 ameliorated the effects of IRI through decreased tubular cell death in proximal tubule cells along with an increase in renal perfusion through a direct vascular effect. These data indicate selective activation of the CB2 receptor by our novel CB2 agonist SMM-295 has therapeutic value in pre-clinical studies and may provide a new target for therapy in the treatment of AKI.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

http://orcid.org/0000-0003-2151-8864

DOI

10.21007/etd.cghs.2020.0502

2020-012-Pressly-DOA.pdf (328 kB)
Declaration of Authorship

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