Activated Protein C Reduces Graft Neutrophil Activation in Clinical Renal Transplantation

Turunen, Arto; Fernández, José A.; Lindgren, L.; Salmela, K.; Kyllönen, L.; Mäkisalo, Heikki; Griffin, John H.; Siitonen, Sanna; Petäjä, Jari; Pesonen, Eero

doi:10.1111/j.1600-6143.2005.00994.x

Cited by 18 publications

(11 citation statements)

References 32 publications

(28 reference statements)

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“…L-selectin is a leukocyte adhesion molecule, the expression of which was also observed after ischemia/reperfusion, and it was decreased in PACAP-treated groups. This is also in accordance with other studies demonstrating that protective strategies can reduce L-selectin expression (Turunen et al 2005). CNTF, a neurotrophic factor, has also been shown to be elevated following kidney ischemia/reperfusion (Yang et al 2001).…”

Section: Discussionsupporting

confidence: 86%

Effects of PACAP on Mitochondrial Apoptotic Pathways and Cytokine Expression in Rats Subjected to Renal Ischemia/Reperfusion

et al. 2010

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Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with highly efficient cytoprotective actions. Its neuroprotective effects are well-known, but PACAP is able to exert similar actions in non-neuronal cells. Recently, we have shown that PACAP prolongs renal ischemic time, decreases mortality, and attenuates tubular degeneration in a rat model of renal ischemia/reperfusion, but the mechanism of renoprotection is not yet known. Therefore, the aim of the present study was to obtain further insight into the renoprotective effects of PACAP by examining its direct effects of PACAP on mitochondrial permeability transition in vitro and on the expression of the anti-apoptotic Bcl-2 and cytokines/chemokines in kidney tissues following 45 and 60 min renal ischemia and reperfusion in vivo. We found that PACAP did not have any direct effect on mitochondrial permeability transition. Cytokine array revealed that the expression of a few cytokines/chemokines was strongly increased after ischemia/reperfusion, which was ameliorated by PACAP treatment. Furthermore, in rats subjected to renal ischemia, PACAP treatment counteracted the ischemia/reperfusion-induced decrease of the anti-apoptotic Bcl-2, both after 45 and 60 min ischemia, as analyzed by Western blot. In summary, we showed that PACAP could attenuate tissue injury involving both anti-inflammatory and anti-apoptotic effects, but not directly acting on mitochondrial permeability transition.

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Section: Discussionsupporting

confidence: 86%

Effects of PACAP on Mitochondrial Apoptotic Pathways and Cytokine Expression in Rats Subjected to Renal Ischemia/Reperfusion

et al. 2010

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“…The upper limit for APC formation may be estimated from APC determinations in various clinical settings where coagulation is known to be activated. In our previous studies the most pronounced and fast enhancements from normal resting APC levels to levels typically ranging from 250% to over 800% of the normal mean were observed during the first minutes of reperfusion in liver transplantation [ 26 ] and during an infusion of antithymocyte globulin, a strong proinflammatory stimulus, in renal transplantation [ 27 ]. Liaw and colleagues recently reported that in acute sepsis patients, despite ongoing activation of coagulation, 25% of patients failed to increase their APC levels above 250% (while 75% had levels ranging from approximately 250 to 800%) [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

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et al. 2006

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“…Using animal with high endogenous APC levels, protection against diabetic nephropathy was observed [122,123]. In renal transplant, Turunen et al, [124] suggested that APC has an anti-inflammatory role in ischemia reperfusion injury. Multiple studies have provided an associate of genetic protein C resistance to an increased risk of early graft loss following kidney transplantation [125][126][127].…”

Section: Role Of Apc In Other Renal Settingsmentioning

confidence: 99%

Activated Protein C and Acute Kidney Injury: Selective Targeting of PAR-1

Gupta

Williams²,

Macias³

et al. 2009

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Protein C is a plasma serine protease that when activated plays a central role in modulating the function of the vascular endothelium and its interface with the innate immune system. Activated protein C (APC) has a dual mechanism of action via the feedback inhibition of thrombin generation, and as an agonist of protease activated receptor-1 (PAR-1). Through different cofactor interactions, this dual mechanism of antithrombotic and cytoprotective activity results in the ability of APC to modulate endothelial dysfunction by blocking cytokine signaling, functional cell adhesion expression, vascular permeability, apoptosis, and modulating leukocyte migration and adhesion. Deficiency in protein C, which occurs during systemic inflammatory activation, is highly associated with organ dysfunction. APC has shown efficacy in a number of preclinical models of thrombosis and ischemia, and the recombinant human APC drotrecogin alfa (activated), reduces mortality in patients with high-risk severe sepsis. The ability of APC to suppress pro-inflammatory pathways and enhance cellular survival suggests that APC plays a key role in the adaptive response to protect the vessel wall from insult and to enhance endothelial, cellular, and organ survival. The focus of this review will be to summarize the emerging data suggesting the potential therapeutic benefit of APC and related members of the pathway in the prevention and treatment of acute kidney injury.

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Activated Protein C Reduces Graft Neutrophil Activation in Clinical Renal Transplantation

Cited by 18 publications

References 32 publications

Effects of PACAP on Mitochondrial Apoptotic Pathways and Cytokine Expression in Rats Subjected to Renal Ischemia/Reperfusion

Effects of PACAP on Mitochondrial Apoptotic Pathways and Cytokine Expression in Rats Subjected to Renal Ischemia/Reperfusion

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Activated Protein C and Acute Kidney Injury: Selective Targeting of PAR-1

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