Date of Award

4-13-2015

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Ping Wang, MD

Second Advisor

Weng-Lang Yang, PhD

Abstract

Ischemia-reperfusion (I/R) injury is a broad clinical entity affecting multiple organs. This dissertation focuses on renal and hepatic I/R, both of which can occur as a complication of direct surgical manipulation or cardiovascular shock. The pathophysiology of I/R injury is comprised of an initial metabolic failure due to ischemia, which extends into reperfusion and is associated with oxidative stress and inflammation. Sirtuin 1 (Sirt1) is a NAD+-dependent energy-sensing enzyme with multiple cellular functions. We hypothesized that pharmacologic Sirt1 activation would restore the cellular energy deficit associated with I/R and thereby attenuate renal and hepatic I/R injury. To investigate this, we employed animal models of renal and hepatic I/R. Additionally, we developed a hypoxia-reoxygenation (H/R) injury model using renal epithelial cells and hepatocytes to gain further mechanistic insights. Animals treated with SRT1720, a Sirt1 activator, were protected against I/R-induced tissue injury, inflammation, and oxidative stress, in both the renal and hepatic I/R models. Pharmacologic Sirt1 activation was associated with an increase in mitochondrial mass and ATP levels after I/R. In cell culture, SRT1720 induced an increase in mitochondrial mass and activity, and ATP levels after H/R. Sirt1 activation was also associated with an increase in the autophagy salvage pathway in the liver after I/R. This was validated in hepatocytes after H/R, where we elucidated the dependence of the Sirt1-mediated enhancement in autophagy on mitochondrial activity. Thus, pharmacologic Sirt1 activation may be a promising therapeutic strategy in patients suffering from renal and hepatic I/R injury.

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