title: CXCR₄antagonism as a therapeutic approach to prevent acute kidney injury.
abstract: We examined whether antagonism of the CXCR₄receptor ameliorates the loss of renal function following ischemia-reperfusion. CXCR₄is ubiquitously expressed on leukocytes, known mediators of renal injury, and on bone marrow hematopoietic stem cells (HSCs). Plerixafor (AMD3100, Mozobil) is a small-molecule CXCR₄antagonist 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 h after reperfusion, as were tissue injury and cell death. Plerixafor prevented the renal increase in the proinflammatory 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 analog of plerixafor, was similarly renoprotective. Four weeks postreperfusion, long-term effects included diminished fibrosis, inflammation, and ongoing renal injury. The mechanism by which CXCR₄inhibition ameliorates AKI is due to modulation of leukocyte infiltration and expression of proinflammatory chemokines/cytokines, rather than a HSC-mediated effect. The data suggest that CXCR₄antagonism with plerixafor may be a potential option to prevent AKI.
authors: Tissue Protection and Repair Unit, Renal Science, Genzyme R&D Center, Framingham, Massachusetts; anna.zuk@genzyme.com.
authors: A
authors: A
authors: Zuk
authors: Tissue Protection and Repair Unit, Renal Science, Genzyme R&D Center, Framingham, Massachusetts;
authors: M
authors: M
authors: Gershenovich
authors: Tissue Protection and Repair Unit, Renal Science, Genzyme R&D Center, Framingham, Massachusetts;
authors: Y
authors: Y
authors: Ivanova
authors: Pharmacology and Preclinical Development, Genzyme R&D Center, Framingham, Massachusetts; and.
authors: R T
authors: RT
authors: MacFarland
authors: Immune-Mediated Disease Research, Genzyme R&D Center, Framingham, Massachusetts.
authors: S P
authors: SP
authors: Fricker
authors: Tissue Protection and Repair Unit, Renal Science, Genzyme R&D Center, Framingham, Massachusetts;
authors: S
authors: S
authors: Ledbetter
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology / Q000517:prevention & control*; D000818:Animals; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007677:Kidney Function Tests; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000276:immunology / Q000517:prevention & control*
chemical_list: D001596:Benzylamines; C575935:CXCL12 protein, rat; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011725:Pyridines; D019718:Receptors, CXCR4; C088327:plerixafor
keywords: chemokine; immune modulation; renal ischemia-reperfusion