Following ischemic injury, dedifferentiated cells appear to migrate into regions of denuded basement membrane, repopulate and repair the injured tubule. Kidney injury molecule-1 (KIM-1) expression is markedly upregulated in surviving proximal epithelial cells in post-ischemic injury and in the dedifferentiated and dividing cells at the free edge of the wound in an in vitro """"""""scratch-induced injury"""""""" model. The ectodomain of KIM-1 is cleaved and can be detected in the urine of patients with acute tubular injury. It can also be detected in the culture medium of cells expressing this protein. KIM-1 expression results in increased binding of bone marrow cells to renal epithelial cells. The chemokine, stromal derived factor-1 (SDF-1) is constitutively expressed in bone marrow stromal cells and kidney. Studies reported decreased expression of SDF-1 and an increased expression of CXCR4 in renal cell carcinoma, indicating CXCR4, like KIM-1, is overexpressed in dedifferentiated cells. Many studies have shown that SDF-1/CXCR4 interactions play an important role in stem cell homing in the bone marrow. It has been shown recently that bone marrow cells (BMCs) contribute to repair of the ischemically injured renal tubule. We have found that after bone marrow transplantation in which x-gal-positive BMCs injected into an irradiated host mouse, x-gal positive cells were found in the recipient kidney that express proximal tubular marker gp330 after renal I/R-induced injury, suggesting BMCs can migrate to the injured site and differentiate into renal epithelial cells. Our preliminary studies in vitro showed that GFP-labeled BMCs in a scratch-induced injury model demonstrated morphological changes and a significant increase of GFP-positive cells at the site of scratch injury. These results suggest KIM-1 may play roles on homing of BMCs in renal injury. Nevertheless, the mechanism of BMCs homing is not fully understood. We will focus on studying the: (1) functional role of KIM-1 in homing of BMCs in injured renal tubule; (2) functional role of SDF-1/CXCR4 in homing of BMCs in injured renal tubule as well as the relationships between KIM-1 and SDF-1/CXCR4; (3) differential gene expression using DNA microarrays to determine the transcriptional program that coordinates migration and repopulation of BMCs. This study may provide new insight on the role of KIM-1 and BMCs in renal tubular injury. KIM-1 may be important in the process of BMC homing.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Rankin, Tracy L
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Brigham and Women's Hospital
United States
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