Kidney Injury Molecule-1 in Epithelial Repair

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Kidney injury molecule-1 (KIM-1) is the most up regulated protein in proximal tubular epithelial cells in various states characterized by epithelial cell dedifferentiation: ischemia, toxic renal injury, and renal cell carcinoma. We have cloned, and generated monoclonal and polyclonal antibodies to, the human, mouse, pig, dog, zebrafish and rat KIM-1. The KIM-1 ectodomain is cleaved and found in the urine of patients with acute kidney injury or renal cell carcinoma and is a sensitive and specific biomarker for kidney injury qualified by the FDA for preclinical safety studies and currently used in many clinical safety studies. We have discovered that KIM-1 transforms kidney epithelial cells into semiprofessional phagocytes making it the first nonmyeloid phosphatidylserine receptor. A mutant mouse lacking an extracellular domain that is important for phagocytosis and a transgenic mouse with Kim-1 expression in the renal tubule have important phenotypes supporting a critical role for this protein in acute and chronic kidney disease. The goal of this proposal is to further characterize the functional role of KIM-1 during acute and chronic injury to the kidney. We hypothesize that KIM-1 reduces the early inflammatory response to ischemic injury as it mediates uptake of apoptotic and necrotic debris from the damaged proximal tubule. In Specific Aim 1 we will characterize and evaluate the phagocytic function of KIM-1 in protection of the kidney exposed to ischemia or toxins. A mutant mouse that is defective in phagocytosis sustains increased injury to the kidney in response to ischemia or cisplatin. The effects of Kim-1 on autophagy, inflammation and the innate immune response will be explored. The contributions of various extracellular and intracellular domains of KIM-1 on phagocytosis and autophagy will be evaluated. In our second specific aim we will explore our hypothesis that KIM-1's interactions with calreticulin on the cell surface of apoptotic and necrotic cell modulate the immunogenicity of cell death associated with acute kidney injury. A considerable number of patients with chronic kidney disease have elevated levels of KIM-1 protein in their urine and kidney tissue. In the third Specific Aim we will analyze the role of persistent KIM-1 expression on inflammation and chronic fibrosis. We have created a transgenic mouse which expresses low levels of Kim-1 in the kidney tubule. This mouse develops severe tubulointerstitial inflammatory disease, anemia, and cardiac hypertrophy and dies at 4-6 months of age with chronic renal failure. This is a novel model of chronic kidney disease and we hypothesize that chronic KIM-1 expression is maladaptive. We will explore the molecular processes responsible for this impressive kidney disease phenotype including the role of chronic KIM-1 expression in cell cycle arrest. In summary understanding the function of KIM-1 will provide important insight into the role of this protein in injury and repair processes of the kidney, and may identify KIM-1 as an important therapeutic target not only for acute and chronic renal disease but also for malignant transformation of the epithelial cell.