All ETDs from UAB

Advisory Committee Chair

Anupam Agarwal

Advisory Committee Members

Subhashini Bolisetty

Michal Mrug

Chad Steele

Thomas Ryan

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


The kidneys are complex, multi-faceted organs that are responsible for regulatory processes, such as fluid homeostasis, hormone production, blood pressure regulation, and systemic toxin removal. Sudden disruption of these processes by acute kidney injury (AKI) causes rapid decline in renal function as well as significant morbidity and mortality. AKI is a significant clinical concern, affecting up to 13.3 million people globally each year and has the propensity to progress to chronic kidney disease (CKD), though the mechanism remains undefined. One reason for this is due to the lack of understanding of models used to study both AKI and CKD, hindering their clinical application. This dissertation focuses in part on the undiscovered etiology of the AKI to CKD transition as well as prospective on the physiological and pathophysiological roles of contributing cell types and factors. An important component of AKI includes destabilization of heme proteins and subsequent cellular stress. To combat this, heme catabolism is initiated by heme oxygenase-1 a highly inducible antioxidant. Ferritin, a well-conserved iron storage protein, is co-induced during heme catabolism and is composed of 24-subunits of two types: light chain (FtL) and heavy chain (FtH). The latter possesses ferroxidase activity, which converts cytotoxic ferrous iron to its safe ferric form. AKI causes perturbations in iron metabolism and protection from ferrous iron toxicity depends on FtH. Therefore, our objective was to define the role of myeloid-specific FtH (FtHLysM-/-) expression during AKI. We report that myeloid-FtH deletion exacerbated ischemia-reperfusion injury (IR) and cell death as early as day 2 post-IR. Due to derangements in iron homeostasis observed in FtHLysM-/- mice during AKI, we hypothesized that inhibition of ferroptosis, or iron-mediated cell death, using ferrostatin-1 would attenuate AKI in myeloid-FtH deficient mice. Indeed, we report amelioration of injury ferrostatin-1 treated FtHLysM-/- mice compared to vehicle controls, highlighting a crucial role for myeloid FtH in protecting against ferroptosis after renal IR. The data presented in this dissertation demonstrate novel insights into the etiology of AKI to CKD disease progression and furthermore suggest an important role for FtH in mitigating ferroptosis in AKI.



To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.