OR25-5 The Chemokine Receptor CXCR4 And Its Ligand, CXCL12, Are Coexpressed In the Adrenal Cortex, Suggesting Roles in Adrenocortical Homeostasis And Disease

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR25-Signaling Originating from Membrane Receptors
Basic/Translational
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:15 PM
Room 133 (Moscone Center)
Xin Xu*1, Eva Szarek2, Moses O. Evbuomwan1, Zhanzhuo Li1, David H. McDermott1, Stefania Pittaluga1, Constantine A Stratakis2 and Joshua M. Farber1
1NIH, 2National Institutes of Health (NIH), Bethesda, MD
CXCR4 and its chemokine ligand, CXCL12, have been implicated in directing the migration of primordial germ cells during organogenesis and are responsible for the retention of hematopoietic cells in bone marrow. Although CXCR4 was found to be expressed in normal human adrenal cortex (and not in the medulla), its role in adrenal physiology and disease is unknown. We studied the potential involvement of CXCR4 in adrenal homeostasis, and in adrenocortical disorders. By immunohistochemistry using a well characterized rabbit monoclonal anti-CXCR4 antibody, which shows the appropriate pattern of surface staining in paraffin-embedded tissue, we found that CXCR4 was highly expressed on zona glomerulosa cells, in both mouse and human. In mouse adrenal cortex, in situ hybridization and immunohistochemistry revealed that CXCL12 mRNA and protein, respectively, were expressed near the adrenal capsule, correlating with the site of CXCR4 expression. Moreover, using a novel radiolabeled form of the CXCR4 antagonist, 64Cu-plerixafor, we found accumulation of the antagonist in the mouse adrenal following i.v. injection, consistent with surface expression of CXCR4 at this site. Effects of CXCR4 blockade on adrenal function were studied by continuous in vivo administration of plerixafor to mice for 6 weeks via osmotic pumps. Plerixafor treatment had no effect on blood aldosterone and corticosterone levels. In human samples, immunohistochemistry revealed high levels of CXCR4 expression in aldosterone-producing adenomas and hyperplasias. In addition, tumor cells of cortisol-producing adenomas (variably) and adrenal hyperplasias (invariably), both micro-and macro-nodular forms, also strongly expressed  CXCR4. There was a positive correlation between CXCR4 expression and aldosterone production, with the exception of the lesions originating from cells at the corticomedullary junction. Correlation with cortisol secretion is currently being studied. Together, our data show that CXCR4 and CXCL12 are constitutively co-expressed in similar regions of the adrenal cortex, consistent with a physiological role in cell-cell interactions at this site. Our data also suggest roles for CXCR4 and CXCL12 in the pathophysiology of adrenocortical disorders.

Nothing to Disclose: XX, ES, MOE, ZL, DHM, SP, CAS, JMF

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