All ETDs from UAB

Advisory Committee Chair

Christian Faul

Advisory Committee Members

Anupam Agarwal

James F George

Louis Justment

Brittany N Lasseigne

Jennifer S Pollack

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In the United States, acute kidney injury (AKI) affects nearly 20% of all intensive care unit patients. Additionally, over a third of Americans aged 50 or older suffer from stage 3 chronic kidney disease (CKD) or higher. AKI and CKD are encompassing terms for many etiologies and pathological processes that affect different regions of the kidney but converge at tissue inflammation and fibrosis. Macrophages perform vital homeostatic functions and can initiate or ameliorate inflammation and fibrosis. As the largest component of the kidney immune system, kidney resident macrophages (KRMs) have been implicated in both disease propagation and mitigation, yet the specific functions of KRMs remains unclear. I hypothesized the known heterogeneity of macrophage functions was representative of a more complex KRM population than has been previously considered. To this end, this work identifies multiple KRM subpopulations that are transcriptionally and spatially distinct. Following AKI, subpopulations alter their location and transcriptional profile in differential responses to injury. In human AKI samples this work identifies orthologous KRM subpopulations, along with a subpopulation unique to humans that expresses the transcriptional profile of activated microglia. iv AKI and CKD result in the downregulation of major histocompatibility complex II (MHC II) by a subset of KRMs in mice and humans. The universal appearance following injury has led to the identification of this subpopulation as kidney injury associated (KIA) cells. In AKI, the absence of MHC II correlates with the expression of a wound healing profile by KIA cells in the location of greatest injury. With the increased clarity on the location and function of KRM subpopulations provided in this work, they are an excellent potential therapeutic option. The spatial restriction of KRM subpopulations would allow for targeted therapies to specific regions of the kidney. Depending on the injury response, therapies should either enhance or ablate the subpopulation’s function. KIA cells provide a unique AKI therapeutic target as they are restricted to the site of injury and may aid in recovery. The identification of orthologous populations across species will expedite the translation of murine research into clinical trials and help to focus future research efforts.

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