All ETDs from UAB

Advisory Committee Chair

Bradley K Yoder

Advisory Committee Members

Anupam Agarwal

Michal Mrug

Laurie E Harrington

Chad H Steele

James F George

Document Type

Dissertation

Date of Award

2018

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Renal cysts are a pathological condition that can lead to end-stage renal failure and death. The mechanisms that underlie renal cyst development are under active investigation, and emerging evidence has revealed defects in a number of proteins required for cilia assembly or signaling, such as intraflagellar transport (IFT) proteins and the polycystins. Characterization of mice harboring conditional IFT mutations suggests that the rate of cyst formation is dependent upon the timing of cilia loss. Induction of cilia loss in juvenile mice results in rapid cyst development, while induction of cilia loss in adult mice leads to a slower progressing form of cystic disease. Interestingly, rapid cyst formation can be initiated in adult-induced IFT mutants by ischemic reperfusion (IR) injury, suggesting a possible role for inflammation in cyst development. This hypothesis is further supported by a recent finding showing that liposome clodronate (LC)-mediated depletion of phagocytic macrophages reduces severity of cystic disease and improves renal function. However, the underlying mechanisms connecting injury response, cilia dysfunction, and cyst formation remain poorly defined. Furthermore, the reasons for the discrepant in cystogenic rates between juvenile and adult-induced cilia mutants are not understood. To address these questions, here I have investigated potential connections between primary cilia-associated cystogenesis and altered inflammatory responses. This study tested the hypothesis that the primary cilia present on the renal epithelium function in an inflammatory response pathway that regulates resident macrophage and T cell recruitment, proliferation, expansion, and polarization during both renal maturation and injury-induced cystogenesis. Results presented in this dissertation show that membrane-bound CSF-1 (mbCSF-1) from renal tubular epithelial cells is a predominant contributor to resident macrophage proliferation and accumulation in the kidney. In addition, we identify a specific subset of juvenile-like resident macrophages that localize adjacent to renal cysts and are associated with rapid cyst formation. More importantly, we show that renal injury induces reprogramming of adult resident macrophages in the kidney towards a juvenile-like phenotype. These phenotypic differences in macrophages likely underlie the discrepancy in the rate of cyst progression in juvenile- and adult-induced cilia mutant mice. The immune response can be divided into two main types: innate and adaptive responses. The major components of the innate immune system are epithelial, macrophage and innate lymphocytes. The adaptive immune system, on the other hand, is comprised of T and B lymphocytes. The experimental evidence suggests that accumulation of lymphocytes is a feature of cystic kidneys. Therefore, we also assessed the contribution of T cells to cyst progression. We show that a number of different T cell subtypes are increased in multiple cystic models and report the occurrence of a shift in T cell subtypes present during the early and advanced stages of cyst formation. In addition, we also show that adaptive immune cells are critical for cyst formation, and depletion of adaptive immune cells in cilia mutant Rag1-/- mice regards cyst formation. This work sheds new light on our understanding of how immune cells contribute to the rate of cyst formation in diseases associated with cilia dysfunction and suggests novel targets for therapeutic intervention.

Share

COinS