Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)


Drug Discovery and Biomedical Sciences


College of Graduate Studies

First Advisor

Thomas A. Dix

Second Advisor

Craig C. Beeson

Third Advisor

Rick G. Schnellmann

Fourth Advisor

Zhi Zhong

Fifth Advisor

Robin C. Muise-Helmericks

Sixth Advisor

Mike Wyatt


Dysfunctional mitochondria are a primary pathological consequence of acute kidney injury (AKI). Mitochondrial homeostasis is disrupted up to 144 h after ischemia-reperfusion (I/R) induced-AKI in the renal cortical tissue of mice. Stimulation of mitochondrial biogenesis in renal cells after oxidant injury restores mitochondrial function. The primary goals of this project were to identify novel pharmacological compounds capable of inducing mitochondrial biogenesis in the renal proximal tubule and evaluate if this induction would promote the recovery of mitochondrial and/or renal function after in vivo AKI. The secondary goal was to employ our mitochondrial approach for drug discovery towards identifying a novel treatment for a different disease state, skeletal muscle atrophy. Stimulation of the G-protein couple receptor (GPCR) family in response to physiological stress results in the downstream activation of effectors, which upregulates the expression and activity of PGC-1α and subsequently activates the mitochondrial biogenic program. Pharmacological agonism of both the stimulatory GPCR (β2-AR) and the inhibitory (A1AR) GPCR family via full and partial agonists resulted in the stimulation of mitochondrial biogenesis in the renal proximal tubule. The A1AR partial agonist CVT-2759 was superior to the full agonist CCPA in stimulating mitochondrial biogenesis in the proximal tubule. Acute kidney injury (AKI), by induction of ischemia-reperfusion (I/R), in mice produced persistent proximal tubule damage, which resulted in minimal recovery of kidney and mitochondrial function at 144 h post injury. Tubule pathology was characterized histologically by the presence of presence of necrosis. Renal dysfunction and injury was evidence by robust increases in serum creatinine and KIM-1 expression. In addition, mitochondrial OXPHOS proteins were suppressed and dysfunctional. Treatment with formoterol, a potent, highly specific, and long-acting -β2-AR agonist, restored renal function, rescued renal tubules from injury, and diminished necrosis after I/R-induced AKI. Concomitantly, formoterol stimulated mitochondrial biogenesis and restored the expression and function of mitochondrial proteins. Skeletal muscle atrophy remains a clinical problem in numerous pathological conditions. β2-AR receptor agonists, such as formoterol, are capable of inducing mitochondrial biogenesis and skeletal muscle hypertrophy. Recently, atomoxetine, an FDA approved norepinephrine reuptake inhibitor, was positive in a cellular assay for mitochondrial biogenesis. Using a mouse model of dexamethasone-induced skeletal muscle atrophy we determined that atomoxetine prevents skeletal muscle atrophy via a non-canonical PGC-1α signaling mechanism. In addition, we determined that formoterol selectively induces the PGC-1α4 splice variant, which initiates a discrete gene program resulting in skeletal muscle hypertrophy. Taken together, we determined that pharmacological stimulation of mitochondrial biogenesis via formoterol is capable of promoting faster recovery of mitochondrial function, which is associated with accelerated recovery of overall kidney function after maximal kidney dysfunction is established. Overall, we have demonstrated that our drug discovery approach is effective in identifying pharmacological compounds capable of inducing mitochondrial biogenesis and other nuclear regulators of metabolism. This approach proves beneficial in defining novel therapies for disease states that are characterized by dysfunctional mitochondria.


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