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Exogenous pentraxin-3 inhibits the reactive oxygen species-mitochondrial and apoptosis pathway in acute kidney injury.

ABSTRACT: Pentraxin-3 (PTX3) is a long-form member of the pentraxin family of proteins that has been studied in inflammatory diseases and in various organs. We found that PTX3 protects kidney cells during ischemia and proinflammatory acute kidney injury. The aim of this study was to develop an in vitro experimental model of acute kidney injury and to analyze the protective mechanism of exogenous recombinant PTX3. In this study, cells of the HK-2 renal tubular cell line were treated with a calcium ionophore (A23187), which induced injury by increasing intracellular calcium concentrations and inducing calpain activity and the generation of reactive oxygen species. Exposure of cells to PTX3 significantly attenuated these effects. In addition, the activity of caspase-3 and PARP-1 were decreased in ischemic cells exposed to exogenous recombinant PTX3. PTX3 stabilized the mitochondrial membrane potential and suppressed apoptosis, resulting in the protection of renal tubular cells from ischemic injury.

SUBMITTER: Lee HH

PROVIDER: S-EPMC5909599 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Exogenous pentraxin-3 inhibits the reactive oxygen species-mitochondrial and apoptosis pathway in acute kidney injury.

Lee Hyung Ho HH Kim Sook Young SY Na Joon Chae JC Yoon Young Eun YE Han Woong Kyu WK

PloS one 20180419 4

Pentraxin-3 (PTX3) is a long-form member of the pentraxin family of proteins that has been studied in inflammatory diseases and in various organs. We found that PTX3 protects kidney cells during ischemia and proinflammatory acute kidney injury. The aim of this study was to develop an in vitro experimental model of acute kidney injury and to analyze the protective mechanism of exogenous recombinant PTX3. In this study, cells of the HK-2 renal tubular cell line were treated with a calcium ionophor ...[more]

PMID: 29672566

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Project description:Background The metabolite succinate accumulates during cardiac ischemia. Within 5 minutes of reperfusion, succinate returns to baseline levels via both its release from cells and oxidation by mitochondrial complex II. The latter drives reactive oxygen species (ROS) generation and subsequent opening of the mitochondrial permeability transition (PT) pore, leading to cell death. Targeting succinate dynamics (accumulation/oxidation/release) may be therapeutically beneficial in cardiac ischemia-reperfusion (IR) injury. It has been proposed that blocking MCT1 (monocarboxylate transporter 1) may be beneficial in IR injury, by preventing succinate release and subsequent engagement of downstream inflammatory signaling pathways. In contrast, herein we hypothesized that blocking MCT1 would retain succinate in cells, exacerbating ROS generation and IR injury. Methods and Results Using the mitochondrial ROS probe mitoSOX and a custom-built murine heart perfusion rig built into a spectrofluorometer, we measured ROS generation in situ during the first moments of reperfusion. We found that acute MCT1 inhibition enhanced mitochondrial ROS generation at reperfusion and worsened IR injury (recovery of function and infarct size). Both of these effects were abrogated by tandem inhibition of mitochondrial complex II, suggesting that succinate retention worsens IR because it drives more mitochondrial ROS generation. Furthermore, using the PT pore inhibitor cyclosporin A, along with monitoring of PT pore opening via the mitochondrial membrane potential indicator tetramethylrhodamine ethyl ester, we herein provide evidence that ROS generation during early reperfusion is upstream of the PT pore, not downstream as proposed by others. In addition, pore opening was exacerbated by MCT1 inhibition. Conclusions Together, these findings highlight the importance of succinate dynamics and mitochondrial ROS generation as key determinants of PT pore opening and IR injury outcomes.

Dataset Information

Exogenous pentraxin-3 inhibits the reactive oxygen species-mitochondrial and apoptosis pathway in acute kidney injury.

Publications

Exogenous pentraxin-3 inhibits the reactive oxygen species-mitochondrial and apoptosis pathway in acute kidney injury.

Similar Datasets

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