Research Award Recipients

Examining Renal Capsule Macrophages as Critical Mediators of Repair in Acute Kidney Injury

Lay Abstract

BACKGROUND: Chronic kidney disease is characterized by loss of normal kidney function over a long period of time, leading to an accumulation of harmful metabolites in the body. This can cause toxicity in other organs and often requires transplantation. Immune cells generate inflammation within diseased tissues and can exacerbate disease progression. Understanding cellular interactions during the progression of kidney disease provides opportunities for slowing degeneration and improving outcomes. Macrophages are a type of innate immune cell that reside within all tissues, patrolling for foreign threats and playing key roles in tissue development and homeostasis. We have demonstrated a high level of macrophage heterogeneity exists within tissues, including the kidney, with macrophage subsets demonstrating unique activities and functions. Specifically, we have identified a subset with a conserved embryonic origin capable of long-term self-renewal with roles in tissue repair and regeneration. Until recently, these macrophages were thought to be absent in the kidney, yet recent advancements have identified their presence in the kidney capsule. The kidney capsule is a fibrous tissue encapsulating the kidney parenchyma, that has little known role. Although the capsule is vastly understudied, previous work suggested that the capsule itself has a role in recovery from acute kidney injury (AKI) and that cells are capable of re-localization from the capsule to the parenchyma. However, the mechanisms by which the capsule is protective to acute injury, and the cell types involved, are unknown.

PURPOSE: Our data indicates kidney capsule macrophages are themselves a heterogenous population containing three main populations with different self-renewal properties, similar to other tissues. Unlike the kidney parenchyma, capsule macrophages are dependent on fibroblast derived growth factors, suggesting the capsule is a unique niche which maintains these cells. We hypothesize that kidney capsule macrophages play an important role in tissue homeostasis and repair, similar to capsule macrophage recently identified in the liver.

METHOD: As leaders in tissue macrophage biology, we will incorporate genetic fate mapping models to understand the developmental relationship capsule macrophages have to inflammatory monocyte-derived macrophages. We will use the renal ischemia-reperfusion injury model (a mouse model of AKI) and visualize capsule macrophage migration using intravital microscopy. We will specifically deplete kidney capsule macrophages to assess their role in tissue repair and use single cell transcriptomics to gain insight into the mechanisms by which capsule macrophages respond to injury.

ANTICIPATED OUTCOMES: This work will expand our understanding of a novel subset of immune cell that resides in the kidney capsule. Our preliminary data suggests capsule macrophages are very similar to an embryonic-derived subset of pro-reparative macrophages found in other tissues. Thus, we anticipate animals that lack capsule macrophages, or capsule macrophage specific growth factors, to exhibit poor injury recovery and decreased renal function in response to AKI.

PATIENT ENGAGEMENT: As a pre-clinical study utilizing animal models of disease, patient engagement is not incorporated into the current proposal.

RELEVANCE TO PATIENTS/COMMUNITY: Kidney disease impacts one in ten Canadians. Deeper knowledge into mechanisms of kidney immunology provide new directions for researchers to anticipate, avert, and address disease. By furthering scientific understanding of cellular mechanisms behind kidney disease and pursuing the possibility of therapeutic intervention through immune-based therapies, this research aims to create opportunities for improving patient outcomes.

CONCLUSION: Overall, these studies form the foundation for future work to examine the molecular mechanisms by which capsule macrophages mediate repair, advancing our knowledge of kidney immunology and the functional role of the kidney capsule. By incorporating our expertise in macrophage subset dynamics, we hope to identify novel mediators to limit kidney inflammation while preserving immune mechanisms of repair.