Advisor(s)
Anupam Agarwal
James George
Committee Member(s)
Bradley Yoder
Brittany Lasseigne
Christopher Willey
Subhashini Bolisetty
School
College of Arts and Sciences
Document Type
Dissertation
Department (new version)
Biology
Date of Award
9-9-2024
Degree Name
Doctor of Philosophy (PhD)
Abstract
The lymphatic vascular system, tasked with managing interstitial fluid homeostasis, clearing cellular debris, and trafficking immune cells, is a promising yet largely untapped area for therapeutic intervention in kidney diseases. Clinically, kidney biopsies of patients with acute kidney injury (AKI) and chronic kidney disease (CKD) show evidence of injury-associated lymphangiogenesis. Recent pre-clinical studies have established that manipulation of the lymphangiogenic response greatly impacts the pathophysiology of serval kidney diseases. However, conflicting results in the literature, unresolved knowledge gaps, and technical challenges hinder the development of lymphatic-modifying therapeutics. Here, we interrogate the long-term effects of ischemia-reperfusion and aging in AKI and the transition from AKI to CKD. Utilizing a comprehensive approach incorporating advanced three-dimensional tissue cytometry and transcriptomic analyses unveiled three distinct phases of age-independent lymphatic responses that occur in the 9 months following AKI in a murine model of bilateral ischemia-reperfusion injury (BIRI): early acute lymphangiogenesis, intermediate regression, and late-stage lymphangiogenesis associated with increased fibrillar collagen deposition, Ccl21a expression, and CCR7+ tertiary lymphoid structure development. We identified Ccl21a as an important marker gene for kidney lymphatic endothelial cells using single-cell and -nucleus transcriptomics datasets. Further developing the methodologies available to study kidney lymphatics, we also present an optimized antibody-based approach for visualizing organ-level lymphatic network structures in the kidney using confocal microscopy. Three-dimensional reconstruction and quantification revealed that acute stage lymphangiogenesis in adult mice subjected to BIRI involves changes to not only kidney lymphatic volume, but also kidney lymphatic branching architecture. Overall, this work advances our understanding and capacity to study the complex relationships among lymphatic remodeling, fibrosis, and immune regulation in both kidney health and disease.
ProQuest ID
Recommended Citation
Ghajar-Rahimi, Gelare, "Unraveling The Lymphatic Landscape In The Normal And Injured Kidney" (2024). All ETDs from UAB. 7569.
https://digitalcommons.library.uab.edu/etd-collection/7569
