All ETDs from UAB

Advisory Committee Chair

David M Pollock

Advisory Committee Members

Jennifer S Pollock

Bradley Yoder

Anupam Agarwal

Jeffrey Lebensburger

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Sickle cell disease (SCD) is a commonly inherited genetic blood disorder that causes hypoxia-induced polymerization of mutant hemoglobin resulting in erythrocyte sickling, transient microvascular occlusion, ischemic injury, and end-organ damage. Systemic endothelial dysfunction and vaso-occlusive episodes observed in SCD are particularly deleterious to the kidney, where the hypoxic, hyperosmotic environment of the medulla makes it particularly susceptible to ischemic injury. Over recent decades, chronic kidney disease has emerged as a significant contributor to mortality and morbidity in SCD patients. Despite a growing interest in the importance of sickle cell nephropathy (SCN), therapeutic options are limited and much remains undiscovered regarding their mechanism. Although initially developed as a cancer chemotherapy agent, hydroxyurea has become the staple of care for the treatment and management of SCD due to its reported fetal hemoglobin-inducing qualities and ability to reduce the frequency of vaso-occlusive episodes. Studies have demonstrated the clinical efficacy of hydroxyurea in reducing renal injury in SCD, yet the exact mechanism has yet to be determined. Endothelin 1(ET-1) is a vasoactive peptide shown to be upregulated in SCD patients and may contribute to the development of disease complications. Enhanced ET-1 signaling via endothelin receptor type A (ETA) activation has been shown to contribute to the development and progression of SCN. Blocking ETA receptor activity reduces renal injury in SCD, yet little is known about the mechanism. The purpose of this dissertation is to elucidate therapeutic mechanisms behind hydroxyurea and selective ETA antagonist treatment in SCN. These studies provide compelling evidence that improved NO bioavailability via reduced arginase activity serves as a contributing mechanism to the therapeutic effects of hydroxyurea in SCN. Conversely, selective ETA blockade provides NO-independent nephroprotection in SCD. Interestingly, both treatments improve anemia status and attenuate hemolysis in SCD. Overall, this dissertation provides evidence both hydroxyurea and selective ETA antagonist converge on the same mechanistic pathway, but differ in their effects on nitric oxide signaling in SCD. In addition, these studies provide evidence that the arginase pathway is an underappreciated mechanism in SCN that could be a potential therapeutic target for drug development.

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