CXCR4 antagonism as a therapeutic approach to prevent acute kidney injury

Żuk, Anna; Gershenovich, Michael; Ivanova, Yordanka; MacFarland, Ron; Fricker, Simon P.; Ledbetter, Steven

doi:10.1152/ajprenal.00685.2013

Cited by 38 publications

(39 citation statements)

References 64 publications

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“…It is possible that the disparity between our findings and those of other investigators maybe secondary to differences in our animal model. Nonetheless, in agreement with other studies, the absence of an SDF-1 gradient did not affect the anti-inflammatory effects of AMD3100 [16]. …”

Section: Discussionsupporting

confidence: 92%

CXCR4 Blockade Attenuates Hyperoxia-Induced Lung Injury in Neonatal Rats

et al. 2015

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Background: Lung inflammation is a key factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Stromal-derived factor-1 (SDF-1) and its receptor chemokine receptor 4 (CXCR4) modulate the inflammatory response. It is not known if antagonism of CXCR4 alleviates lung inflammation in neonatal hyperoxia-induced lung injury. Objective: We aimed to determine whether CXCR4 antagonism would attenuate lung injury in rodents with experimental BPD by decreasing pulmonary inflammation. Methods: Newborn rats exposed to normoxia (room air, RA) or hyperoxia (FiO₂ = 0.9) from postnatal day 2 (P2) to P16 were randomized to receive the CXCR4 antagonist, AMD3100 or placebo (PL) from P5 to P15. Lung alveolarization, angiogenesis and inflammation were evaluated at P16. Results: Compared to the RA pups, hyperoxic PL pups had a decrease in alveolarization, reduced lung vascular density and increased lung inflammation. In contrast, AMD3100-treated hyperoxic pups had improved alveolarization and increased angiogenesis. This improvement in lung structure was accompanied by a decrease in the macrophage and neutrophil counts in the bronchoalveolar lavage fluid and reduced lung myeloperoxidase activity. Conclusion: CXCR4 antagonism decreases lung inflammation and improves alveolar and vascular structure in neonatal rats with experimental BPD. These findings suggest a novel therapeutic strategy to alleviate lung injury in preterm infants with BPD.

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Section: Discussionsupporting

confidence: 92%

CXCR4 Blockade Attenuates Hyperoxia-Induced Lung Injury in Neonatal Rats

et al. 2015

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“…Neutrophils and monocytes mediate the acute phase within the first 24 h of injury (55), whereas studies in mouse models support a role for T and B lymphocytes, not present in large numbers (55), in the evolution of renal injury (53). Inhibition of leukocyte infiltration into the kidney by the small molecule plerixafor, an antagonist of the leukocyte CXCR4 chemokine receptor (56), ameliorates the loss in renal function, decreasing renal injury, cell death, and long-term fibrosis. Furthermore, when the cholinergic anti-inflammatory pathway mediated by the α7 nicotinic acetylcholine receptor on splenic CD4 + T cells is activated with ultrasound prior to ischemia-reperfusion injury (57), there is renoprotection.…”

Section: Pathophysiologymentioning

confidence: 99%

“…Cellular senescence is detected following renal ischemia reperfusion injury by the senescence marker β-galactosidase, with greater senescence in aged kidneys (8). It is possible that following AKI, cellular senescence may contribute to a proinflammatory milieu to promote fibrogenesis, as this correlates with increased leukocyte infiltration and enhanced expression of chemokines and cytokines in the chronic phase following acute injury (8, 56, 67). …”

Section: Pathophysiologymentioning

confidence: 99%

Acute Kidney Injury

2016

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Acute kidney injury (AKI) is a global public health concern associated with high morbidity, mortality, and healthcare costs. Other than dialysis, no therapeutic interventions reliably improve survival, limit injury, or speed recovery. Despite recognized shortcomings of in vivo animal models, the underlying pathophysiology of AKI and its consequence, chronic kidney disease (CKD), is rich with biological targets. We review recent findings relating to the renal vasculature and cellular stress responses, primarily the intersection of the unfolded protein response, mitochondrial dysfunction, autophagy, and the innate immune response. Maladaptive repair mechanisms that persist following the acute phase promote inflammation and fibrosis in the chronic phase. Here macrophages, growth-arrested tubular epithelial cells, the endothelium, and surrounding pericytes are key players in the progression to chronic disease. Better understanding of these complex interacting pathophysiological mechanisms, their relative importance in humans, and the utility of biomarkers will lead to therapeutic strategies to prevent and treat AKI or impede progression to CKD or end-stage renal disease (ESRD).

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“…11,58,59 To quantify reactivity in kidney tubules, four to six random fields of the outer medulla or cortex per section per animal were photographed at 203 followed by Metamorph analysis (Molecular Devices, Sunnyvale, CA). Data are expressed as mean6SEM.…”

Section: Morphologic Analysismentioning

confidence: 99%

Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations

Clements¹,

Gershenovich²,

Chaber³

et al. 2016

Journal of the American Society of Nephrology

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Macrophages are a heterogeneous cell type implicated in injury, repair, and fibrosis after AKI, but the macrophage population associated with each phase is unclear. In this study, we used a renal bilateral ischemiareperfusion injury mouse model to identify unique monocyte/macrophage populations by differential expression of Ly6C in CD11b + cells and to define the function of these cells in the pathophysiology of disease on the basis of microarray gene signatures and reduction strategies. Macrophage populations were isolated from kidney homogenates by fluorescence-activated cell sorting for whole genome microarray analysis.

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CXCR4 antagonism as a therapeutic approach to prevent acute kidney injury

Abstract: Zuk A, Gershenovich M, Ivanova Y, MacFarland RT, Fricker SP, Ledbetter S. CXCR4 antagonism as a therapeutic approach to prevent acute kidney injury.

Cited by 38 publications

References 64 publications

CXCR4 Blockade Attenuates Hyperoxia-Induced Lung Injury in Neonatal Rats

CXCR4 Blockade Attenuates Hyperoxia-Induced Lung Injury in Neonatal Rats

Acute Kidney Injury

Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations

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