Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation

Daemen, M.A.R.C.; Veer, Cornelis van ’t; Denecker, Geertrui; Heemskerk, V.H.; Wolfs, Tim G. A. M.; Clauss, Matthias; Vandenabeele, Peter; Buurman, Wim A.

doi:10.1172/jci6974

Cited by 524 publications

(439 citation statements)

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“…15,16,18 In addition, two main pathways of death receptor-dependent and mitochondria-mediated apoptosis have been implicated in I/R-induced apoptosis, and both pathways activate downstream effector caspase-3. 4 We thus further examined caspase-3 activation in kidneys of WT and GC-G Ϫ/Ϫ mice by Western blot analysis using an antibody that specifically reacted with the active, cleaved forms of caspase-3.…”

Section: Decreased Number Of Polymorphonuclear Cells and Renal Myelopmentioning

confidence: 99%

Disruption of Guanylyl Cyclase-G Protects against Acute Renal Injury

Lin

Cheng²,

Hou

et al. 2008

Journal of the American Society of Nephrology

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The membrane forms of guanylyl cyclase (GC) serve as cell-surface receptors that synthesize the second messenger cGMP, which mediates diverse cellular processes. Rat kidney contains mRNA for the GC-G isoform, but the role of this receptor in health and disease has not been characterized. It was found that mouse kidney also contains GC-G mRNA, and immunohistochemistry identified GC-G protein in the epithelial cells of the proximal tubule and collecting ducts. Six hours after ischemia-reperfusion (I/R) injury, GC-G mRNA and protein expression increased three-fold and remained upregulated at 24 h. For determination of whether GC-G mediates I/R injury, a mutant mouse with a targeted disruption of the GC-G gene (Gucy2g) was created. At baseline, no histologic abnormalities were observed in GC-G Ϫ/Ϫ mice. After I/R injury, elevations in serum creatinine and urea were attenuated in GC-G Ϫ/Ϫ mice compared with wild-type controls, and this correlated with less tubular disruption, less tubular cell apoptosis, and less caspase-3 activation. Measures of inflammation (number of infiltrating neutrophils, myeloperoxidase activity, and induction of IL-6 and P-selectin) and activation of NF-B were lower in GC-G Ϫ/Ϫ mice compared with wild-type mice. Direct transfer of a GC-G expression plasmid to the kidneys of GC-G Ϫ/Ϫ mice resulted in a dramatically higher mortality after renal I/R injury, further supporting a role for GC-G in mediating injury. In summary, GC-G may act as an early signaling molecule that promotes apoptotic and inflammatory responses in I/R-induced acute renal injury.

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Section: Decreased Number Of Polymorphonuclear Cells and Renal Myelopmentioning

confidence: 99%

Disruption of Guanylyl Cyclase-G Protects against Acute Renal Injury

Lin

Cheng²,

Hou

et al. 2008

Journal of the American Society of Nephrology

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“…Relatively recent information suggests that necrosis and apoptosis are governed by similar mechanisms, and contrary to earlier belief they may share common molecular pathways (Shimizu et al, 1996;Gottlieb & Engler, 1999). Moreover, if the high energy phosphate reserves are exhausted, cells undergoing apoptosis can switch to secondary necrosis (Leist & Nicotera, 1997;Daemen et al, 1999). Thus, the precise mechanism(s) by which caspase inhibitors lead to limitation of infarction is not certain.…”

mentioning

confidence: 96%

Caspase inhibition and limitation of myocardial infarct size: protection against lethal reperfusion injury

Mocanu

Baxter

Yellon

2000

British J Pharmacology

191

105

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Ischaemia-reperfusion injury causes cell death by both necrosis and apoptosis. Caspase activation is a major event in apoptosis. We therefore examined the e ect of caspase inhibitors during reperfusion upon myocardial infarction. Rat isolated hearts were subjected to 35 min coronary occlusion and 120 min reperfusion. Treatment groups were perfused with caspase inhibitors during early reperfusion. We assessed a non-selective caspase inhibitor (Z-VAD×fmk, 0.1 mM), a caspase-8 inhibitor (Z-IETD×fmk, 0.07 mM), a caspase-9 inhibitor (Z-LEHD×fmk, 0.07 mM) and a caspase-3 inhibitor (Ac-DEVD×cmk, 0.07 mM). All caspase inhibitors limited infarct size (infarct-risk ratio per cent: control 38.5+2.6; Z-VAD×fmk 24.6+3.4; Z-LEHD×fmk 19.3+2.4; Z-IETD×fmk 23.0+5.4; AcDEVD×cmk 27.8+3.3; P50.05 when compared with control value, 1-way ANOVA). We conclude that caspase inhibition during early reperfusion protects myocardium against lethal reperfusion injury.

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“…As it has been demonstrated, the HGF antiapoptotic effect aids early renal recovery, since less I/R-induced apoptosis prevents the development of inflammation and organ dysfunction. 38 Even though ischemia-induced HGF is physiologically synthesized as a natural repair process, its overexpression induced by gene therapy supports cytoprotective actions through that antiapoptotic effect. As our results show, this gene therapy reduced apoptotic cells: the only apoptotic cells were tubular cells.…”

Section: Discussionmentioning

confidence: 99%