All ETDs from UAB

Advisory Committee Chair

Anupam Agarwal

Advisory Committee Members

Michal Mrug

Janusz Kabarowski

Louis Justement

Rakesh Patel

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Acute kidney injury (AKI) can be a devastating condition, affecting up to sixty percent of critically ill patients in the United States. Despite the fact that AKI is associated with an increased risk of chronic kidney disease (CKD) and mortality, there are no targeted therapies available to treat it. Kidney resident macrophages (KRM) are likely necessary for healing and resolution of animal models of AKI. However, there remains a gap in knowledge regarding how KRM effect this function. The purpose of my thesis was to elucidate lineage relationships and functionally relevant adaptations of KRM and monocyte-derived mononuclear phagocytes (infiltrative MP) in response to AKI. I performed these studies with the goal of identifying avenues for intervention in the inflammatory response to AKI in patients. As a result of these studies, I have: (i) established tissue residence of KRM in the healthy state and studied their role in animal models of the AKI to CKD transition (ii) applied ischemia-reperfusion (IR)-AKI to parabiotic mice and found KRM do not differentiate from infiltrative MP (iii) used transgenic mice to determine the ability of bone marrow hematopoietic precursors to fill an empty KRM niche (iv) found MHCII is dynamically regulated on KRM, demonstrating a developmental switch and a return to the MHCII-negative phenotype after injury (v) observed that KRM return to a developmental transcriptional profile after injury enriched in canonical Wnt signaling. These studies are significant for having added fundamental knowledge to the understanding of the renal MP system. Our studies provide rationale for lineage-specific interventions in MP-mediated inflammation after AKI. Due to the fact that KRM and infiltrative MP are unique from each other with respect to lineage and transcriptional profile, these cell types should be targeted independently. KRM are an exciting target for nanomedicine, biologics, and cell-based therapy approaches to treating AKI. Keywords: acute kidney injury, chronic kidney disease, macrophage, tissue resident macrophage, mononuclear phagocyte, ontogeny, MHC class II

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