Role of KIM-1 ectodomain shedding in acute kidney injury
Co-Applicant(s): Aaron Haig, Lauryl Nutter
Lay Abstract
The diagnosis of acute kidney injury (AKI) is made when there is a sudden decrease in kidney function or urine production. AKI affects about 20% of hospitalized patients worldwide and can be triggered by various factors, including severe infections that decrease blood flow to the kidneys, cardiovascular surgery, certain medications like antibiotics or chemotherapies, or blockages in urine flow, such as from an enlarged prostate. While many patients with AKI eventually regain full kidney function, others may develop chronic kidney damage and scarring, leading to the need for dialysis. Currently, there are no effective treatments to reverse AKI or prevent its progression to chronic kidney damage. Therefore, our study aims to explore the molecular mechanisms that contribute to chronic damage following an AKI episode to develop preventive strategies against kidney failure. We have identified a molecule known as Kidney Injury Molecule-1 (KIM-1), which is produced by kidney cells during AKI but is absent in healthy kidneys.
Our previous research has indicated that KIM-1 plays a pivotal role in repairing tissue damage after AKI. However, new findings from our group suggest that prolonged presence of KIM-1, particularly after severe injury, may inadvertently cause kidney scarring and lead to chronic kidney disease, contradicting its usual reparative role. This complex behavior of KIM-1, varying between repair and scarring based on the severity of the injury, highlights the importance of understanding the specific conditions under which KIM-1 operates. An interesting characteristic of KIM-1 is that it can be "shed" (or released) from the surface of kidney cells into the urine. The biological purpose of this shedding and how it influences the dual nature of KIM-1 in promoting repair or causing scarring is still unclear. We hypothesize that the shedding of KIM-1 is a natural defense mechanism to minimize scarring after an AKI event.
To investigate this theory, we plan to conduct comprehensive experiments using mice that have been genetically modified so that they do not shed KIM-1. By comparing these genetically modified mice with normal mice in response to AKI, we aim to discern whether inhibiting KIM-1 shedding can indeed prevent the development of kidney scarring. Our work promises to significantly advance the understanding of KIM-1's role in AKI and potentially uncover therapeutic strategies that favour kidney repair over scarring following a severe AKI incident.
