Date of Award

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Drug Discovery and Biomedical Sciences

College

College of Graduate Studies

First Advisor

Craig C. Beeson

Second Advisor

Sherine S. L. Chan

Third Advisor

C. James Chou

Fourth Advisor

Louis M. Luttrell

Fifth Advisor

Rick G. Schnellmann

Abstract

Acute kidney injury (AKI) is the transient loss of renal function following an insult. Despite high incidence and mortality, therapy for AKI is limited to supportive care and renal replacement therapy. The induction of mitochondrial biogenesis (MB) accelerates recovery of renal function in animal models of AKI. We have identified that the beta-2 adrenergic receptor (β2AR) agonist formoterol induces MB in renal proximal tubule cells (RPTC); however, not all β2AR agonists induce MB. We hypothesized that formoterol activates a distinct signaling pathway in RPTC to induce MB and accelerate recovery of renal function. In cultured RPTC, we found that formoterol activates a Gβγ-Akt-eNOS-cGMP pathway. Clenbuterol, a β2AR agonist that does not induce MB, did not activate this pathway. Formoterol, but not clenbuterol, increased mRNA expression of PGC-1a and NDUFS1; mtDNA copy number; and FCCP-uncoupled respiration at 24 h in RPTC. Inhibition of Gβγ, Akt, NOS, and guanylate cyclase prevented formoterol-induced increases in these markers of MB. To assess the role of proximal tubule β2AR in formoterol-induced recovery of renal function, a mouse with proximal tubule-specific deletion of the β2AR (γGT-Cre:ADRB2Flox/Flox) was generated. Following bilateral renal ischemia reperfusion, γGT-Cre:ADRB2Flox/Flox and wild-type controls (ADRB2Flox/Flox) were treated once-daily with 0.3 mg/kg formoterol beginning at 24 h. At 144 h post-injury, ADRB2Flox/Flox mice treated with formoterol had improved renal function and increased markers of MB relative to vehicle controls, while γGT-Cre:ADRB2Flox/Flox mice treated with formoterol did not. Furthermore, transmission electron microscopy demonstrated that in ADRB2Flox/Flox mice, but not in γGT-Cre:ADRB2Flox/Flox mice, formoterol increased mitochondrial number and density relative to vehicle controls. Together, these data demonstrate that formoterol activates a Gβγ-Akt-eNOS-cGMP to induce MB in RPTC and that following AKI, formoterol acts on RPTC β2AR to induce MB and accelerate recovery of renal function

Rights

All rights reserved. Copyright is held by the author.

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