Thesis Format
Integrated Article
Degree
Master of Science
Program
Microbiology and Immunology
Supervisor
Gunaratnam. Lakshman
Abstract
Kidney injury molecule-1 (KIM-1) is upregulated on injured renal proximal tubule epithelial cells (PTECs) during acute kidney injury (AKI) and can transform PTECs into semi-professional phagocytes to remove apoptotic cells. KIM-1 also induces autophagy, which facilitates efficient phagocytosis. Currently, KIM-1 signalling contributes to tissue injury or repair remains unclear. We hypothesized that KIM-1 interacts with novel intracellular proteins to regulate cellular processes including autophagy and cell death during tissue injury. Using KIM-1 co-immunoprecipitation and mass spectrometry, we identified the PI3K regulatory subunit 4 (PIK3R4) as a KIM-1-interacting protein. We discovered that KIM-1 stimulation with apoptotic cells increased autophagy. Silencing KIM-1 in PTECs enhanced necrotic cell death and inhibited cell proliferation, which was mediated by PIK3R4. We propose that KIM-1 inhibits PIK3R4-mediated cell proliferation to prevent further exposure to injury. This knowledge may help to develop therapeutic strategies to accelerate renal recovery after AKI by targeting KIM-1 or its interacting proteins.
Summary for Lay Audience
Acute kidney injury, defined as the sudden loss of kidney function, is commonly seen in hospitalized patients and is associated with long-term complications, including death. Patients who experience severe kidney injury are at risk of developing chronic kidney diseases, which can ultimately lead to kidney failure. In this thesis, we studied how Kidney Injury Molecule 1 (KIM-1), implicated in acute kidney injury, may help kidney cells respond to injury or promote tissue repair. When the kidney cells are injured, they exhibit increased levels of KIM-1 on the cell surface. KIM-1 has been shown to induce autophagy, a protective cellular process that helps to break down and recycle damaged cellular contents to provide new building blocks and energy to maintain homeostasis. However, the relationship between KIM-1 and autophagy in kidney cells remained unknown. We performed a series of experiments to identify the protein(s) that may play a role in the regulation of autophagy through their interaction with KIM-1 and understand how KIM-1 may enhance renal recovery together by regulating these proteins. This was an important research question because it can help clinicians find ways to preserve kidney function and increase patient survival after acute kidney injury. Using biochemical strategies, we used KIM-1 as a “bait” to capture a previously unknown protein called PIK3R4, which was already known to be involved in autophagy. Our results further showed that KIM-1 may protect injured kidney cells from death. This knowledge may help the scientific community better understand the protective mechanisms of KIM-1 in human kidney cells and inform physicians on potential strategies to exploit the role of KIM-1 to mitigate the detrimental effects of acute kidney injury on patients.
Recommended Citation
Li, Yilong, "PIK3R4 as a potential regulator of Kidney Injury Molecule-1-mediated cell signalling in proximal tubule cells" (2025). Electronic Thesis and Dissertation Repository. 10747.
https://ir.lib.uwo.ca/etd/10747
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.