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Expression and Targeting of CX₃CL1 (Fractalkine) in Renal Tubular Epithelial Cells

Anne M. Durkan^*,, R. Todd Alexander^*,, Guang-Ying Liu, Min Rui, Giuseppe Femia and Lisa A. Robinson^*,

^* Division of Nephrology and Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada

Address correspondence to: Dr. Lisa A. Robinson, Division of Nephrology, Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada. Phone: 416-813-7654 ext. 1745; Fax: 416-813-6271; E-mail: lisa.robinson{at}sickkids.ca

Received for publication August 15, 2006. Accepted for publication October 19, 2006.

The chemokine CX₃CL1 plays a key role in glomerulonephritis and can act as both chemoattractant and adhesion molecule. CX₃CL1 also is upregulated in tubulointerstitial injury, but little is known about the subcellular distribution and function of CX₃CL1 in renal tubular epithelial cells (RTEC). Unexpectedly, it was found that CX₃CL1 is expressed predominantly on the apical surface of tubular epithelium in human renal transplant biopsy specimens with acute rejection or acute tubular necrosis. For studying the targeting of CX₃CL1 in polarized RTEC, MDCK cells that expressed untagged or green fluorescent protein–tagged CX₃CL1 were generated. The chemokine was present on the apical membrane and in subapical vesicles. Apical targeting of CX₃CL1 was not due to signals that were conferred by its intracellular domain, to associations with lipid rafts, or to O-glycosylation but, rather, depended on N-linked glycosylation of the protein. With the use of fluorescence recovery after photobleaching, it was found that CX₃CL1 is immobile in the apical membrane. However, CX₃CL1 partitioned with the triton-soluble rather than -insoluble cellular fraction, indicating that it is not associated directly with the actin cytoskeleton or with lipid rafts. Accordingly, disruption of rafts through cholesterol depletion did not render CX₃CL1 mobile. For exploration of potential functions of apical CX₃CL1, binding of CX₃CR1-expressing leukocytes to polarized RTEC was examined. Leukocyte adhesion to the luminal surface was enhanced significantly when CX₃CL1 was present. These data demonstrate that CX₃CL1 is expressed preferentially on the apical membrane of RTEC and suggest a novel function for the chemokine in recruitment and retention of leukocytes in tubulointerstitial inflammation.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673