Search

Enhanced protection from renal ischemia: Reperfusion injury with A2A -adenosine receptor activation and PDE 4 inhibition. Background. We previously demonstrated in rats and mice that agonists of A2A -adenosine receptors (A2A -ARs) reduce renal injury following ischemia-reperfusion. We now extend these studies and examine the effects of ATL-146e (formerly DWH-146e), an A2A -AR agonist, and rolipram, a type IV phosphodiesterase (PDE 4) inhibitor, on murine renal injury following ischemia-reperfusion. Methods. C57BL/6 mice were treated with rolipram, ATL-146e, or both compounds combined and were subjected to renal ischemia for 32 minutes and reperfusion for 24 to 48 hours. In vitro studies were performed on suspended and adhering human neutrophils. Results. Continuous delivery of rolipram or ATL-146e during reperfusion reduced renal injury in a dose-dependent manner. Maximal protection was observed when ATL-146e was infused for six hours during reperfusion. Elevated plasma creatinine and myeloperoxidase activity produced by ischemia-reperfusion were reduced by rolipram (0.1 ng/kg/min) and ATL-146e (10 ng/kg/min) by up to approximately 60% and 70%, respectively. Co-infusion of both compounds produced a maximum reduction of plasma creatinine of approximately 90% and myeloperoxidase activity. In vitro studies on suspended and adhering human neutrophils demonstrated that selective stimulation of A2A -ARs by ATL-146e increased cAMP accumulation, reduced oxidative activity of activated neutrophils, and decreased activated neutrophil adherence. These responses were potentiated by rolipram. Conclusions. We conclude that the combined infusion of ATL-146e and rolipram leads to enhanced renal tissue protection from ischemia-reperfusion by mechanisms that may include reduced neutrophil adherence/recruitment and release of reactive oxygen species. [ABSTRACT FROM AUTHOR]

T cells are activated by antigen-independent as well as antigen-dependent mechanisms during ischemia-reperfusion injury to the kidney. In the current issue, a study by Savransky et al. suggests that antigen-dependent activation of T-cell receptors further contributes to the pathogenesis of ischemia-reperfusion injury.Kidney International (2006) 69, 208–210. doi:10.1038/sj.ki.5000128 [ABSTRACT FROM AUTHOR]

Sphingosine-1-phosphate (S1P), produced by sphingosine kinase 1 (SphK1) or kinase 2 (SphK2), mediates biological effects through intracellular and/or extracellular mechanisms. Here we determined a role for these kinases in kidney injury of wild-type mice following ischemia–reperfusion. SphK1 but not SphK2 mRNA expression and activity increased in the kidney following injury relative to sham-operated animals. Although SphK1−/− mice had no alteration in renal function following injury, mice with a disrupted SphK2 gene (SphK2tr/tr) had histological damage and impaired function. The immune-modulating pro-drug, FTY720, an S1P agonist failed to provide protection in SphK2tr/tr mice. Injured kidneys of these mice showed increased neutrophil infiltration and neutrophil chemokine expression along with a 3- to 5-fold increase in expression of the G-protein-coupled receptor S1P3 compared to heterozygous SphK2+/tr mice. Kidney function and reduced vascular permeability were preserved in S1P3−/− compared to S1P3+/− mice after ischemia–reperfusion injury, suggesting increased S1P3 mRNA may play a role in the injury of SphK2tr/tr mice. Our study suggests that constitutive expression of SphK2 may contribute to reduced ischemia–reperfusion injury of the kidney, and its absence may enhance injury due to increased neutrophil infiltration and S1P3 activation. We also confirm that SphK2 is necessary to mediate the protective effects of FTY720.Kidney International (2009) 75, 167–175; doi:10.1038/ki.2008.400; published online 29 October 2008 [ABSTRACT FROM AUTHOR]

Chemokines and their receptors such as CCR2 and CX3CR1 mediate leukocyte adhesion and migration into injured tissue. To further define mechanisms of monocyte trafficking during kidney injury we identified two groups of F4/80-positive cells (F4/80(low) and F4/80(high)) in the normal mouse kidney that phenotypically correspond to macrophages and dendritic cells, respectively. Following ischemia and 3 h of reperfusion, there was a large influx of F4/80(low) inflamed monocytes, but not dendritic cells, into the kidney. These monocytes produced TNF-alpha, IL-6, IL-1alpha and IL-12. Ischemic injury induced in CCR2(-/-) mice or in CCR2(+/+) mice, made chimeric with CCR2(-/-) bone marrow, resulted in lower plasma creatinine levels and their kidneys had fewer infiltrated F4/80(low) macrophages compared to control mice. CX3CR1 expression contributed to monocyte recruitment into inflamed kidneys, as ischemic injury in CX3CR1(-/-) mice was reduced, with fewer F4/80(low) macrophages than controls. Monocytes transferred from CCR2(+/+) or CX3CR1(+/-) mice migrated into reperfused kidneys better than monocytes from either CCR2(-/-) or CX3CR1(-/-) mice. Adoptive transfer of monocytes from CCR2(+/+) mice, but not CCR2(-/-) mice, reversed the protective effect in CCR2(-/-) mice following ischemia-reperfusion. Egress of CD11b(+)Ly6C(high) monocytes from blood into inflamed kidneys was CCR2- and CX3CR1-dependent. Our study shows that inflamed monocyte migration, through CCR2- and CX3CR1-dependent mechanisms, plays a critical role in kidney injury following ischemia reperfusion. [ABSTRACT FROM AUTHOR]

Chemokines and their receptors such as CCR2 and CX3CR1 mediate leukocyte adhesion and migration into injured tissue. To further define mechanisms of monocyte trafficking during kidney injury we identified two groups of F4/80-positive cells (F4/80low and F4/80high) in the normal mouse kidney that phenotypically correspond to macrophages and dendritic cells, respectively. Following ischemia and 3 h of reperfusion, there was a large influx of F4/80low inflamed monocytes, but not dendritic cells, into the kidney. These monocytes produced TNF-α, IL-6, IL-1α and IL-12. Ischemic injury induced in CCR2−/− mice or in CCR2+/+ mice, made chimeric with CCR2−/− bone marrow, resulted in lower plasma creatinine levels and their kidneys had fewer infiltrated F4/80low macrophages compared to control mice. CX3CR1 expression contributed to monocyte recruitment into inflamed kidneys, as ischemic injury in CX3CR1−/− mice was reduced, with fewer F4/80low macrophages than controls. Monocytes transferred from CCR2+/+ or CX3CR1+/− mice migrated into reperfused kidneys better than monocytes from either CCR2−/− or CX3CR1−/− mice. Adoptive transfer of monocytes from CCR2+/+ mice, but not CCR2−/− mice, reversed the protective effect in CCR2−/− mice following ischemia-reperfusion. Egress of CD11b+Ly6Chigh monocytes from blood into inflamed kidneys was CCR2- and CX3CR1-dependent. Our study shows that inflamed monocyte migration, through CCR2- and CX3CR1-dependent mechanisms, plays a critical role in kidney injury following ischemia reperfusion.Kidney International (2008) 74, 1526–1537; doi:10.1038/ki.2008.500; published online 8 October 2008 [ABSTRACT FROM AUTHOR]