Response of kidney resident macrophages to proximal tubule injury

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PROJECT SUMMARY This NIH F30 application describes a four-year plan for mentored research and career development for the PI, Matthew Cheung. The scientific premise of this proposal is focused on the role of kidney resident macrophages and their responses to acute kidney injury (AKI). AKI is a major complication affecting up to 20% of hospitalized and 60% of critically ill patients. Despite the high mortality rate and frequency of occurrence, targeted therapies to treat AKI have not been successfully developed. The innate immune system, particularly macrophages, are important in the pathogenesis and healing in AKI and will likely be an important component of future therapies. Studies involving kidney resident macrophages (KRMs) are increasing in number as preliminary studies suggest that they are crucial in renal homeostasis and healing from injury. KRMs modulate the response to AKI, but the mechanism of their contribution remains unknown. Here, we will elucidate the molecular and cellular mechanisms that govern how KRMs maintain and restore renal function after injury. Our preliminary single-cell RNA sequencing data suggest that the KRM population consists of several undescribed subpopulations with distinct functions. Spatial transcriptomics shows that these subpopulations reside in distinct microenvironments and at least one appears to migrate to the proximal tubules in response to injury. We have also found that KRMs in both mice and humans express high levels of the complement protein and pattern recognition molecule C1q. Our central hypothesis is KRM subpopulations have a defined transcriptional response to renal injury and react to PTEC damage in a C1q-dependent manner. We will test this hypothesis through single-cell and spatial transcriptomics and a variety of in vitro and in vivo experiments, including the use of mice deficient in C1q expression in KRMs and a model of proximal tubule-specific injury. Understanding the involvement of the various KRM subpopulations and of C1q, one of the most abundant proteins produced by KRMs, will have a significant impact on our understanding of mechanisms that can be targeted for the treatment of AKI. The proposed training plan for the PI is sponsored by co-mentors Anupam Agarwal, MD, and James George, PhD. Included in the training plan are experiences that will help Matthew develop in three major areas: 1) rigorous immunological research in acute kidney injury, which includes developing familiarity with the existing literature, critical evaluation of data, and training in the responsible conduct of research; 2) rigorous training in advanced bioinformatics and next-generation sequencing analysis and 3) career and professional development, including grant and manuscript writing, scientific communications, and the translation of research findings to clinical applications. This proposal drives the development of skills required for rigorous scientific research critical immunology and advanced bioinformatics skills necessary for the PI’s future career as a nephrology physician-scientist focused on precision medicine and immune-mediated kidney diseases.