CXCR4 Antagonism as a Therapeutic Approach to Prevent Acute Kidney Injury.

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CXCR4 Antagonism as a Therapeutic Approach to Prevent Acute Kidney Injury.

Am J Physiol Renal Physiol. 2014 Jul 30;

Authors: Zuk A, Gershenovich M, Ivanova Y, MacFarland RT, Fricker SP, Ledbetter SR

Abstract
We examined whether antagonism of the CXCR4 receptor ameliorates the loss of renal function following ischemia-reperfusion. CXCR4 is ubiquitously expressed on leukocytes, known mediators of renal injury, and on bone marrow hematopoietic stem cells (HSC). Plerixafor (AMD3100, Mozobil ) is a small molecule CXCR4 antagonist that mobilizes HSCs into the peripheral blood and also modulates the immune response in in vivo rodent models of asthma and rheumatoid arthritis. Treatment with plerixafor before and after ischemic clamping ameliorated kidney injury in a rat model of bilateral renal ischemia-reperfusion. Serum creatinine and blood urea nitrogen were significantly reduced 24 hours after reperfusion, as was tissue injury and cell death. Plerixafor prevented the renal increase in the pro-inflammatory chemokines CXCL1 and CXCL5 and the cytokine IL-6. Flow cytometry of kidney homogenates confirmed the presence of significantly fewer leukocytes with plerixafor treatment; additionally, myeloperoxidase activity was reduced. AMD3465, a monocyclam analogue of AMD3100, was likewise renoprotective. Four weeks post-reperfusion, long-term effects included diminished fibrosis, inflammation and ongoing renal injury. The mechanism by which CXCR4 inhibition ameliorates AKI is due to modulation of leukocyte infiltration and expression of pro-inflammatory chemokines/cytokines, rather than a HSC mediated effect. The data suggest that CXCR4 antagonism with plerixafor may be a potential option to prevent AKI.

PMID: 25080523 [PubMed – as supplied by publisher]

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