Advisory Committee Chair
David Pollock
Advisory Committee Members
Bradley K Yoder
Etty N Benveniste
James S George
Michael Mrug
John M Parant
Document Type
Dissertation
Date of Award
2022
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Polycystic kidney disease (PKD) is one of the most common inherited renal disorders. The most common form, autosomal dominant polycystic kidney disease (ADPKD), affects more than 13 million people around the world, and over 50% of them will develop end-stage renal disease (ESRD). Although ADPKD genetically is caused by mutations of PKD1 or PKD2 genes, there is increasing evidence showing that non-genetic factors such as renal injury and inflammation play important roles in cyst severity and progression in PKD. Macrophages are cells of the innate immune system known to be involved in kidney injury and repair. Data from our lab demonstrated that a subpopulation of macrophages, referred to as tissue resident macrophages, accelerate cyst formation following injury. Whether these resident macrophages also function in cyst formation or progression in spontaneously progressing cystic kidneys in the absence of an external injury was unknown. In this study, I addressed this question and confirmed a pathogenic function for macrophages in cyst progression in PKD without an external injury. More importantly, I identified a unique resident macrophage population expressing CD206 that accumulated in mouse kidneys and in urine samples from ADPKD patients. There was a strong correlation with urinary CD206+ macrophages and disease severity in human PKD patients. These data suggest that CD206+ resident macrophages promote cyst formation and importantly, iv that they could be a clinical biomarker to predict cystic kidney disease progression in patients. My data also addressed the potential mechanism for macrophage accumulation in cystic kidney disease and proposed a unique function of primary cilia in regulating the inflammatory responses during cyst formation. The presence of primary cilia on renal epithelium may influence inflammatory cytokine expression, which drives macrophage accumulation around forming cysts to influence rates of cyst progression. In addition, I investigated the reciprocal interactions between the renal epithelium and immune cells in the cystic kidney using sc-RNAseq. The analysis identified a potential role of a CD4+ T cell population in cyst formation through interactions with macrophages in an injuryaccelerated cystic model, but this was not evident in the non-injured cystic models. In summary, my data emphasized the importance of resident macrophages and T cells in cystic kidney disease. A better understanding about the exact mechanisms involved in cyst development and progression and elucidate how other external factors affecting these processes could lead to promising therapeutic treatments for this devasting disease.
Recommended Citation
Li, Zhang, "Primary Cilia Regulate Inflammation and Macrophage Accumulation During Injury and Cyst Formation in Mouse PKD Models" (2022). All ETDs from UAB. 478.
https://digitalcommons.library.uab.edu/etd-collection/478