Anatomy and Cell Biology – Research Associate Professor
Kidney Institute – Faculty
Anatomy and Cell Biology
Ph.D.: University of Washington, Seattle, WA
Postdoctoral training: Department of Anatomy and Cellular Biology, Harvard Medical School
Publications: Click here
The long-standing focus of my research has been centered on the molecular pathways that regulate cell cycle progression, migration and proliferation in proliferative diseases. Our current studies, which are carried out in collaboration with the laboratory of Dr. Tim Fields, are directed toward understanding the cellular and molecular processes within the renal environment that influence polycystic kidney disease (PKD) progression. PKD is a common, potentially life-threatening genetic disease that is characterized by fluid-filled cysts that develop within the kidneys and grow steadily over decades, leading to both massive enlargement and gross distortion of this organ. Cysts arise and expand due to the abnormal proliferation and fluid secretion of the epithelial cells that line the tubules of the kidney. Expansion of renal cysts in PKD causes compressive injury to the surrounding non-cystic tissues, inducing an inflammatory response that includes the infiltration of lymphocytes and macrophages1. While genetic mutations in the cilia-associated PKD1 or PKD2 genes are primarily responsible for the onset of most examples of PKD, there is accruing evidence that the renal injury due to cyst initiation/expansion and the resultant inflammatory processes that occur in this disease accelerate its progression.
Our lab is interested in the role of the renal inflammatory environment, with a particular focus on macrophages, in PKD progression. Macrophages normally infiltrate tissues in response to infection or injury where they act first to sterilize the environment. Subsequently, they secrete factors that promote repair, cell proliferation and regeneration of damaged tissues. Following tissue repair, further infiltration of these cells no longer occurs, and their numbers decline to that found in the pre-injured state. In PKD kidneys from both humans and mice we have found large numbers of infiltrated renal macrophages and, using a mouse model of PKD, have shown that the presence of these cells contributes to cyst expansion and functional renal decline. In further experiments, we found that macrophages promote the proliferation of PKD cyst cells when co-cultured in vitro, and that these pro-proliferative effects are mediated by soluble factor(s). In addition, we have found that the presence of renal tubule epithelial cells can "program" the macrophages to assume this pro-proliferative phenotype in vitro2. Collectively, these studies suggest that macrophage infiltration persists in PKD, and, while their transient presence in non-PKD kidneys forms an important part of the normal physiologic response to injury, their continued presence in PKD is specifically pathologic, promoting cyst cell proliferation and expansion.
Ongoing projects in the lab are focused on 1) identification of the specific macrophage factors and downstream signaling pathways that promote PKD cyst cell proliferation; 2) elucidation of the mechanism by which renal epithelial cells program the pro-proliferative macrophage phenotype; and 3) identification of the specific factors that mediate renal macrophage recruitment in PKD. To carry out these studies, we employ both in vitro cell culture systems using primary human cells, as well as whole-animal, genetically-altered strains of mice that model PKD. This research is expected to facilitate the achievement of our broader goals, which are to develop therapeutic agents to be used in the clinic that block deleterious macrophage processes in PKD, and, thus, are expected to slow progression of this disease.
 Grantham JJ, Mulamalla S, Swenson-Fields KI. Why kidneys fail in autosomal dominant polycystic kidney disease. Nat Rev Nephrol. 7:556-566, 2011. PMID: 21862990
 Swenson-Fields KI, Vivian CJ , Salah SM, Peda JD, Davis BM, van Rooijen N, Wallace DP, Fields TA. Macrophages promote polycystic kidney disease progression. Kidney Int. 2013 Feb 20. Epub ahead of print. PMID: 23423256