Serine/threonine kinase, Cot/Tpl2, regulates renal cell apoptosis in ischaemia/reperfusion injury

Yaomura, Takaaki; Tsuboi, Naotake; Urahama, Yoshinori; Hobo, Akinori; Sugimoto, Kenji; Miyoshi, Jun; Matsuguchi, Tetsuya; Kannagi, Reiji; Matsuo, Seiichi

doi:10.1111/j.1440-1797.2008.00959.x

Cited by 10 publications

(6 citation statements)

References 20 publications

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“…This finding fits very well with another study reporting decreased megalin mRNA expression in response to I/R. 39 As renal I/R induces the renal formation of cytokines, 40 and may also activate the ERK1/2 pathway, 41,42 it seems likely that the decrease of megalin in response to I/R could also be due to an activation of cytokines and/or the ERK1/2 pathway. In addition, we now found that cubilin expression is also decreased in response to I/R injury.…”

Section: Discussionsupporting

confidence: 90%

Acute endotoxemia in mice induces downregulation of megalin and cubilin in the kidney

Schreiber

Theilig

Schweda

et al. 2012

Kidney International

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Severe sepsis is often accompanied by acute renal failure with renal tubular dysfunction. Albuminuria is a common finding in septic patients and we studied whether it was due to an impairment of proximal tubular endocytosis of filtered albumin. We studied the regulation of megalin and cubilin, the two critical multiligand receptors responsible for albumin absorption, during severe experimental endotoxemia. Lipopolysaccharide (LPS) caused a time- and dose-dependent suppression of megalin and cubilin expression that was paralleled by a decrease in plasma albumin levels and an increase in the urine concentration of albumin in mice. Incubation of rat renal cortical slices with LPS also reduced the mRNA expression of megalin and cubilin. Further, LPS suppressed megalin and cubilin mRNA expression in murine primary proximal tubule cells and decreased the uptake of FITC albumin in these cells. In addition, the increase in urine levels of albumin in response to ischemia/reperfusion-induced acute renal failure was paralleled by a decrease in the expression of megalin and cubilin. Thus, our data indicate that the expression of megalin and cubilin is decreased during experimental endotoxemia and in response to renal ischemia/reperfusion injury. This downregulation may contribute, in part, to an increase in urine levels of albumin during acute renal failure.

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Section: Discussionsupporting

confidence: 90%

Acute endotoxemia in mice induces downregulation of megalin and cubilin in the kidney

Schreiber

Theilig

Schweda

et al. 2012

Kidney International

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“…Although TPL-2 is known to be required for LPS-induced ERK1/2 activation in macrophages, this is the first study to demonstrate increased TPL-2 phosphorylation in the renal cortex in response to systemic endotoxin exposure (Dumitru et al, 2000;Banerjee et al, 2006). A recent study did reveal that TPL-2 knockout mice are protected from kidney ischemia/reperfusion, although this effect was not attributed to the MAPK function of TPL-2 (Yaomura et al, 2008). Fig.…”

Section: Discussionmentioning

confidence: 91%

Suppression of Mitochondrial Biogenesis through Toll-Like Receptor 4–Dependent Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signaling in Endotoxin-Induced Acute Kidney Injury

Smith

Stallons

Collier

et al. 2014

J Pharmacol Exp Ther

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Although disruption of mitochondrial homeostasis and biogenesis (MB) is a widely accepted pathophysiologic feature of sepsisinduced acute kidney injury (AKI), the molecular mechanisms responsible for this phenomenon are unknown. In this study, we examined the signaling pathways responsible for the suppression of MB in a mouse model of lipopolysaccharide (LPS)-induced AKI. Downregulation of peroxisome proliferator-activated receptor g coactivator-1a (PGC-1a), a master regulator of MB, was noted at the mRNA level at 3 hours and protein level at 18 hours in the renal cortex, and was associated with loss of renal function after LPS treatment. LPS-mediated suppression of PGC-1a led to reduced expression of downstream regulators of MB and electron transport chain proteins along with a reduction in renal cortical mitochondrial DNA content. Mechanistically, Toll-like receptor 4 (TLR4) knockout mice were protected from renal injury and disruption of MB after LPS exposure. Immunoblot analysis revealed activation of tumor progression locus 2/mitogen-activated protein kinase kinase/ extracellular signal-regulated kinase (TPL-2/MEK/ERK) signaling in the renal cortex by LPS. Pharmacologic inhibition of MEK/ ERK signaling attenuated renal dysfunction and loss of PGC-1a, and was associated with a reduction in proinflammatory cytokine (e.g., tumor necrosis factor-a [TNF-a], interleukin-1b) expression at 3 hours after LPS exposure. Neutralization of TNF-a also blocked PGC-1a suppression, but not renal dysfunction, after LPS-induced AKI. Finally, systemic administration of recombinant tumor necrosis factor-a alone was sufficient to produce AKI and disrupt mitochondrial homeostasis. These findings indicate an important role for the TLR4/MEK/ERK pathway in both LPS-induced renal dysfunction and suppression of MB. TLR4/MEK/ERK/TNF-a signaling may represent a novel therapeutic target to prevent mitochondrial dysfunction and AKI produced by sepsis.

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“…Mitogen-activated protein kinase-kinase-kinase-8 (MAP3K8, also called TPL-2) can activate both the ERK1/2 and p38 MAP kinases 84 . MAP3K8 regulates renal cell apoptosis in ischemia/reperfusion injury 85 . Herein, MAP3K8 is dowregulated from WI to end of cold storage.…”

Section: Discussionmentioning

confidence: 99%

Dynamic transcriptomic analysis of Ischemic Injury in a Porcine Pre-Clinical Model mimicking Donors Deceased after Circulatory Death

Giraud

Steichen

Allain

et al. 2018

Sci Rep

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Due to organ shortage, clinicians are prone to consider alternative type of organ donors among them donors deceased after circulatory death (DCD). However, especially using these organs which are more prone to graft dysfunction, there is a need to better understand mechanistic events ocuring during ischemia phase and leading to ischemia/reperfusion injuries (IRI). The aim of this study is to provide a dynamic transcriptomic analysis of preclinical porcine model kidneys subjected to ischemic stress mimicking DCD donor. We compared cortex and corticomedullary junction (CMJ) tissues from porcine kidneys submitted to 60 min warm ischemia (WI) followed by 0, 6 or 24 hours of cold storage in University of Wisconsin solution versus control non-ischemic kidneys (n = 5 per group). 29 cortex genes and 113 CMJ genes were significantly up or down-regulated after WI versus healthy kidneys, and up to 400 genes were regulated after WI followed by 6 or 24 hours of cold storage (p < 0.05). Functionnal enrichment analysis (home selected gene kinetic classification, Gene-ontology-biological processes and Gene-ontology-molecular-function) revealed relevant genes implication during WI and cold storage. We uncovered targets which we will further validate as biomarkers and new therapeutic targets to optimize graft kidney quality before transplantation and improve whole transplantation outcome.

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Serine/threonine kinase, Cot/Tpl2, regulates renal cell apoptosis in ischaemia/reperfusion injury

Abstract: Cot/Tpl2 did not function as a member of MAPK family, but as a promoter of apoptosis in IRI. These results suggest that Cot/Tpl2 could be a possible therapeutic target in IRI.

Cited by 10 publications

References 20 publications

Acute endotoxemia in mice induces downregulation of megalin and cubilin in the kidney

Acute endotoxemia in mice induces downregulation of megalin and cubilin in the kidney

Suppression of Mitochondrial Biogenesis through Toll-Like Receptor 4–Dependent Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Signaling in Endotoxin-Induced Acute Kidney Injury

Dynamic transcriptomic analysis of Ischemic Injury in a Porcine Pre-Clinical Model mimicking Donors Deceased after Circulatory Death

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