Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages

Day, Yuan-Ji; Huang, Liping; Zhang, Pengcheng; Linden, Joel; Okusa, Mark D.

doi:10.1152/ajprenal.00378.2004

Cited by 264 publications

(232 citation statements)

References 41 publications

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“…11 Several groups have shown that systemic depletion of phagocytes, including monocytes and macrophages, with liposomal clodronate before I/R decreases morphologic kidney damage and attenuates the increase in blood urea nitrogen (BUN) and creatinine. 11,12 These observations are consistent with the idea that macrophage infiltration augments the inflammatory response and promotes tubular injury. Recent studies in other forms of immune-mediated renal injury raise the possibility that it is the effector phenotype of the recruited macrophages rather than their presence alone that determines the extent of renal parenchymal injury.…”

supporting

confidence: 85%

Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair

Lee¹,

Huen²,

Nishio³

et al. 2011

Journal of the American Society of Nephrology

754

796

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The ischemically injured kidney undergoes tubular cell necrosis and apoptosis, accompanied by an interstitial inflammatory cell infiltrate. In this study, we show that iNos-positive proinflammatory (M1) macrophages are recruited into the kidney in the first 48 hours after ischemia/reperfusion injury, whereas arginase 1-and mannose receptor-positive, noninflammatory (M2) macrophages predominate at later time points. Furthermore, depletion of macrophages before ischemia/reperfusion diminishes kidney injury, whereas depletion at 3 to 5 days after injury slows tubular cell proliferation and repair. Infusion of Ifn␥-stimulated, bone marrowderived macrophages into macrophage-depleted mice at the time of kidney reperfusion restored injury to the level seen without macrophage depletion, suggesting that proinflammatory macrophages worsen kidney damage. In contrast, the appearance of macrophages with the M2 phenotype correlated with the proliferative phase of kidney repair. In vitro studies showed that IFN␥-stimulated, proinflammatory macrophages begin to express markers of M2 macrophages when cocultured with renal tubular cells. Moreover, IL-4 -stimulated macrophages with an M2 phenotype, but not IFN␥-stimulated proinflammatory macrophages, promoted renal tubular cell proliferation. Finally, tracking fluorescently labeled, IFN␥-stimulated macrophages that were injected after injury showed that inflammatory macrophages can switch to an M2 phenotype in the kidney at the onset of kidney repair. Taken together, these studies show that macrophages undergo a switch from a proinflammatory to a trophic phenotype that supports the transition from tubule injury to tubule repair.

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supporting

confidence: 85%

Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair

Lee¹,

Huen²,

Nishio³

et al. 2011

Journal of the American Society of Nephrology

754

796

View full text Add to dashboard Cite

show abstract

“…Renal IR injury is associated with the rapid accumulation of a massive number of neutrophils and monocyte/macrophages in the interstitium of injured kidney (3,22,25,27). Animal studies have shown that macrophage depletion in the mouse or rat attenuates renal IR injury, while adoptive macrophage transfer into these animals reconstitutes renal IR injury (14,22), supporting the important role of macrophages in renal IR injury. Whether PKG has an effect on an innate immune response and kidney inflammation in renal IR injury is not known.…”

Section: Discussionmentioning

confidence: 96%

Overexpression of cGMP-dependent protein kinase I (PKG-I) attenuates ischemia-reperfusion-induced kidney injury

Tong

Maimaitiyiming

et al. 2012

American Journal of Physiology-Renal Physiology

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Overexpression of cGMP-dependent protein kinase I (PKG-I) attenuates ischemia-reperfusion-induced kidney injury. Am J Physiol Renal Physiol 302: F561-F570, 2012. First published December 7, 2011 doi:10.1152/ajprenal.00355.2011.-cGMP-dependent protein kinase (PKG) is a multifunctional protein. Whether PKG plays a role in ischemia-reperfusion-induced kidney injury (IRI) is unknown. In this study, using an in vivo mouse model of renal IRI, we determined the effect of renal IRI on kidney PKG-I levels and also evaluated whether overexpression of PKG-I attenuates renal IRI. Our studies demonstrated that PKG-I levels (mRNA and protein) were significantly decreased in the kidney from mice undergoing renal IRI. Moreover, PKG-I transgenic mice had less renal IRI, showing improved renal function and less tubular damage compared with their wild-type littermates. Transgenic mice in the renal IRI group had decreased tubular cell apoptosis accompanied by decreased caspase 3 levels/ activity and increased Bcl-2 and Bag-1 levels. In addition, transgenic mice undergoing renal IRI demonstrated reduced macrophage infiltration into the kidney and reduced production of inflammatory cytokines. In vitro studies showed that peritoneal macrophages isolated from transgenic mice had decreased migration compared with control macrophages. Taken together, these results suggest that PKG

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“…The functional role of DCs in AKI has been examined using liposomal clodronate. 3,56 In ischemic AKI, clodronate reduced the severity of renal injury, 31,57 whereas in the cisplatin model, clodronate did not affect renal injury. 56 Unfortunately, clodronate is not specific for DCs, which limits the interpretation of these results.…”

Section: Discussionmentioning

confidence: 99%

Renal Dendritic Cells Ameliorate Nephrotoxic Acute Kidney Injury

Tadagavadi¹,

Reeves

2010

Journal of the American Society of Nephrology

139

161

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Inflammation contributes to the pathogenesis of acute kidney injury. Dendritic cells (DCs) are immune sentinels with the ability to induce immunity or tolerance, but whether they mediate acute kidney injury is unknown. Here, we studied the distribution of DCs within the kidney and the role of DCs in cisplatin-induced acute kidney injury using a mouse model in which DCs express both green fluorescence protein and the diphtheria toxin receptor. DCs were present throughout the tubulointerstitium but not in glomeruli. We used diphtheria toxin to deplete DCs to study their functional significance in cisplatin nephrotoxicity. Mice depleted of DCs before or coincident with cisplatin treatment but not at later stages experienced more severe renal dysfunction, tubular injury, neutrophil infiltration and greater mortality than nondepleted mice. We used bone marrow chimeric mice to confirm that the depletion of CD11c-expressing hematopoietic cells was responsible for the enhanced renal injury. Finally, mixed bone marrow chimeras demonstrated that the worsening of cisplatin nephrotoxicity in DC-depleted mice was not a result of the dying or dead DCs themselves. After cisplatin treatment, expression of MHC class II decreased and expression of inducible co-stimulator ligand increased on renal DCs. These data demonstrate that resident DCs reduce cisplatin nephrotoxicity and its associated inflammation.

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Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages

Cited by 264 publications

References 41 publications

Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair

Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair

Overexpression of cGMP-dependent protein kinase I (PKG-I) attenuates ischemia-reperfusion-induced kidney injury

Renal Dendritic Cells Ameliorate Nephrotoxic Acute Kidney Injury

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