Advisor(s)

Bradley Yoder

Committee Member(s)

Alexa Mattheyses
James George
Takamitsu Saigusa
Tanecia Mitchell

Document Type

Dissertation

Date of Award

6-18-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Joint Health Sciences

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder characterized by progressive cyst formation, kidney enlargement, and eventual renal failure. Mutations in PKD1 or PKD2 disrupt polycystin-mediated mechanosensory signaling in renal epithelial cells, altering calcium signaling, epithelial architecture, and cellular homeostasis. Although cyst expansion has historically been attributed to epithelial hyperproliferation or tubule pinching off to form a cyst that no longer remains connected with the tubule, the early physiological and molecular events that initiate cyst formation remain incompletely understood. This dissertation investigates how alterations in tubule flow dynamics and epithelial stress responses contribute to cyst initiation and expansion in polycystic kidney disease. Using inducible Pkd2 mutant mouse models, Chapter 2 examines changes in tubule flow behavior during disease progression. Fluorescent low-molecular-weight dextran uptake assays and intravital imaging of the kidney demonstrate that dilated and cystic tubules remain patent and continue to receive filtrate, indicating that cyst formation does not arise from complete luminal obstruction. Instead, cystic segments exhibit reduced flow velocity and luminal expansion. Sequential dextran labeling further reveals the emergence of newly absorbing epithelial populations over time, suggesting recruitment of additional nephron segments to maintain kidney function as disease progresses. These findings support a model in which renal functional reserve is progressively engaged as polycystin loss disrupts normal mechanosensory signaling and alters nephron workload prior to the onset of cyst formation. Chapter 3 investigates how epithelial cells respond to the loss of polycystin 1 or 2 during cyst initiation and expansion and indicates that cells stress and maladaptive states well before cyst formation. Immunofluorescence analyses reveal persistent nuclear localization of the cyclin-dependent kinase inhibitor p21 (CDKN1A) in precystic, and cyst-lining epithelial cells in Pkd1 and Pkd2 mutant kidneys. Genetic ablation of p21 in Pkd2 mutants results in a marked reduction in cyst burden, demonstrating that p21 is not merely a marker of epithelial stress but an active regulator of cyst progression. These findings support a model in which sustained nuclear p21 stabilizes a stress-adapted epithelial state that promotes cytoskeletal remodeling, and expanding cysts. Together, this work supports an integrated model of PKD progression in which loss of polycystin signaling leads to altered tubule flow dynamics and activation of maladaptive epithelial repair programs. Persistent nuclear p21 enforces a survival-oriented checkpoint that enables stressed epithelial cells to persist and remodel rather than resolve injury. By linking physiological changes in nephron function with molecular mechanisms of epithelial stress adaptation, this dissertation provides new insight into the mechanisms driving cyst initiation and expansion and identifies p21-mediated epithelial reprogramming as a potential therapeutic axis in polycystic kidney disease. These findings challenge the traditional view that cyst expansion is driven primarily by proliferation or tubule obstruction and instead position epithelial stress adaptation as a central driver of disease initiation.

Download

Share

COinS