All ETDs from UAB

Advisory Committee Chair

Anupam Agarwal

Advisory Committee Members

James F Collawn

James F George

Bradley K Yoder

Paul W Sanders

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Acute kidney injury (AKI), defined as the rapid loss of kidney function, is often seen in the setting of multiple organ failure in critically ill patients. Lack of established therapeutic approaches to overcome AKI has lead to unacceptably high incidence of morbidity and mortality in these patients. The molecular mechanisms that lead to AKI often have oxidative stress as a common pathogenic event. The kidney responds by prompt induction of its own anti-oxidant machinery including the highly inducible, anti-inflammatory and anti-apoptotic gene-heme oxygenase-1 (HO-1). This microsomal enzyme degrades pro-oxidant heme, which is released from heme proteins. The cytoprotective properties of HO-1 are not merely due to removal of heme but are also attributed to the beneficial properties of the by-products of the reaction. Biliverdin and bilirubin are potent peoxyl radical scavengers and carbon monoxide has anti-inflammatory and anti-apoptotic properties. This thesis discusses an undiscovered property of HO-1 in AKI, namely autophagy, which is a regulated intracellular degradation system in which cytoplasmic components are directed to the lysosome for breakdown. However, excessive autophagy is deleterious as it may destroy cell contents beyond a certain threshold that would lead to cell death. Therefore, regulation of autophagy during injury is extremely important for survival. The results of this thesis indicate that HO-1 modulates autophagy in renal epithelial cells during AKI and confers cytoprotection. Specifically, mice deficient in HO-1 had increased basal autophagy which upon cisplatin injury led to increased apoptosis. However, overexpression of HO-1 was associated with a delayed autophagic response and decreased apoptosis during injury. Also, HO-1 overexpression resulted in decreased reactive oxygen species (ROS) generation during injury. More importantly, restoring HO-1 expression in HO-1 deficient mice rescued mice from impaired autophagy and increased apoptosis during AKI. It is noteworthy that most of the ROS generation during AKI is attributed to mitochondria. We therefore targeted HO-1 to the mitochondria and rescued renal epithelial cells from loss of mitochondrial integrity, increased ROS accumulation and lipid peroxidation during oxidative stress. These findings demonstrate a novel mechanistic role for HO-1 in limiting oxidative stress and modulating autophagy and provide new avenues for therapeutic approaches in AKI.

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