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

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

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Aim: Cot/Tpl2, a serine/threonine (Ser/Thr) protein kinase, has been classified as a member of the mitogen-activated protein kinase (MAPK) family, and is known to have a pleiotropic role. Many studies have reported the involvement of Cot/Tpl2, mainly as a member of the Toll-like receptor (TLR) 4 signalling pathway in lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) production. At the same time, it is also related to the caspase-dependent apoptotic pathway. Thus, the role of Cot/Tpl2 in ischaemia/reperfusion injury (IRI) in which TNF-α and apoptosis are the major pathogenetic factors was studied. Methods: IRI was induced in wild type (Cot/Tpl2+/+) mice and in Cot/Tpl2-deficient (Cot/Tpl2-/-) mice. The extent of tubular injury and renal function were studied. TNF-α production, neutrophil infiltration and apoptosis were also compared between the two groups. Results: Cot/Tpl2-/- mice had preserved renal function compared with wild type mice in IRI. Although Cot/Tpl2 was phosphorylated in IRI and in the cultured tubular epithelial cells (TEC) after stimulation with LPS and hydrogen peroxide, there were no significant differences in terms of TNF-α production, neutrophil infiltration or MAPK activation between Cot/Tpl2+/+ and Cot/Tpl2-/- mice. In contrast, Cot/Tpl2-/- mice showed obviously reduced terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling positive cells and cleaved caspase-3 positive cells. Furthermore, Cot/Tpl2-deficient TECs demonstrated significantly less caspase-3 activation after hydrogen peroxide stimulation with comparable caspase-9 activation to wild type TEC. Conclusion: 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.

Original languageEnglish
Pages (from-to)397-404
Number of pages8
JournalNephrology
Volume13
Issue number5
DOIs
Publication statusPublished - 01-08-2008
Externally publishedYes

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Protein-Serine-Threonine Kinases
Reperfusion Injury
Apoptosis
Kidney
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinases
Neutrophil Infiltration
Caspase 3
Hydrogen Peroxide
Lipopolysaccharides
Epithelial Cells
Toll-Like Receptor 4
DNA Nucleotidylexotransferase
Caspase 9
Caspases
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Yaomura, Takaaki ; Tsuboi, Naotake ; Urahama, Yoshinori ; Hobo, Akinori ; Sugimoto, Kenji ; Miyoshi, Jun ; Matsuguchi, Tetsuya ; Reiji, Kannagi ; Matsuo, Seiichi ; Yuzawa, Yukio. / Serine/threonine kinase, Cot/Tpl2, regulates renal cell apoptosis in ischaemia/reperfusion injury. In: Nephrology. 2008 ; Vol. 13, No. 5. pp. 397-404.
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title = "Serine/threonine kinase, Cot/Tpl2, regulates renal cell apoptosis in ischaemia/reperfusion injury",
abstract = "Aim: Cot/Tpl2, a serine/threonine (Ser/Thr) protein kinase, has been classified as a member of the mitogen-activated protein kinase (MAPK) family, and is known to have a pleiotropic role. Many studies have reported the involvement of Cot/Tpl2, mainly as a member of the Toll-like receptor (TLR) 4 signalling pathway in lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) production. At the same time, it is also related to the caspase-dependent apoptotic pathway. Thus, the role of Cot/Tpl2 in ischaemia/reperfusion injury (IRI) in which TNF-α and apoptosis are the major pathogenetic factors was studied. Methods: IRI was induced in wild type (Cot/Tpl2+/+) mice and in Cot/Tpl2-deficient (Cot/Tpl2-/-) mice. The extent of tubular injury and renal function were studied. TNF-α production, neutrophil infiltration and apoptosis were also compared between the two groups. Results: Cot/Tpl2-/- mice had preserved renal function compared with wild type mice in IRI. Although Cot/Tpl2 was phosphorylated in IRI and in the cultured tubular epithelial cells (TEC) after stimulation with LPS and hydrogen peroxide, there were no significant differences in terms of TNF-α production, neutrophil infiltration or MAPK activation between Cot/Tpl2+/+ and Cot/Tpl2-/- mice. In contrast, Cot/Tpl2-/- mice showed obviously reduced terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling positive cells and cleaved caspase-3 positive cells. Furthermore, Cot/Tpl2-deficient TECs demonstrated significantly less caspase-3 activation after hydrogen peroxide stimulation with comparable caspase-9 activation to wild type TEC. Conclusion: 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.",
author = "Takaaki Yaomura and Naotake Tsuboi and Yoshinori Urahama and Akinori Hobo and Kenji Sugimoto and Jun Miyoshi and Tetsuya Matsuguchi and Kannagi Reiji and Seiichi Matsuo and Yukio Yuzawa",
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Yaomura, T, Tsuboi, N, Urahama, Y, Hobo, A, Sugimoto, K, Miyoshi, J, Matsuguchi, T, Reiji, K, Matsuo, S & Yuzawa, Y 2008, 'Serine/threonine kinase, Cot/Tpl2, regulates renal cell apoptosis in ischaemia/reperfusion injury', Nephrology, vol. 13, no. 5, pp. 397-404. https://doi.org/10.1111/j.1440-1797.2008.00959.x

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; Reiji, Kannagi; Matsuo, Seiichi; Yuzawa, Yukio.

In: Nephrology, Vol. 13, No. 5, 01.08.2008, p. 397-404.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Serine/threonine kinase, Cot/Tpl2, regulates renal cell apoptosis in ischaemia/reperfusion injury

AU - Yaomura, Takaaki

AU - Tsuboi, Naotake

AU - Urahama, Yoshinori

AU - Hobo, Akinori

AU - Sugimoto, Kenji

AU - Miyoshi, Jun

AU - Matsuguchi, Tetsuya

AU - Reiji, Kannagi

AU - Matsuo, Seiichi

AU - Yuzawa, Yukio

PY - 2008/8/1

Y1 - 2008/8/1

N2 - Aim: Cot/Tpl2, a serine/threonine (Ser/Thr) protein kinase, has been classified as a member of the mitogen-activated protein kinase (MAPK) family, and is known to have a pleiotropic role. Many studies have reported the involvement of Cot/Tpl2, mainly as a member of the Toll-like receptor (TLR) 4 signalling pathway in lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) production. At the same time, it is also related to the caspase-dependent apoptotic pathway. Thus, the role of Cot/Tpl2 in ischaemia/reperfusion injury (IRI) in which TNF-α and apoptosis are the major pathogenetic factors was studied. Methods: IRI was induced in wild type (Cot/Tpl2+/+) mice and in Cot/Tpl2-deficient (Cot/Tpl2-/-) mice. The extent of tubular injury and renal function were studied. TNF-α production, neutrophil infiltration and apoptosis were also compared between the two groups. Results: Cot/Tpl2-/- mice had preserved renal function compared with wild type mice in IRI. Although Cot/Tpl2 was phosphorylated in IRI and in the cultured tubular epithelial cells (TEC) after stimulation with LPS and hydrogen peroxide, there were no significant differences in terms of TNF-α production, neutrophil infiltration or MAPK activation between Cot/Tpl2+/+ and Cot/Tpl2-/- mice. In contrast, Cot/Tpl2-/- mice showed obviously reduced terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling positive cells and cleaved caspase-3 positive cells. Furthermore, Cot/Tpl2-deficient TECs demonstrated significantly less caspase-3 activation after hydrogen peroxide stimulation with comparable caspase-9 activation to wild type TEC. Conclusion: 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.

AB - Aim: Cot/Tpl2, a serine/threonine (Ser/Thr) protein kinase, has been classified as a member of the mitogen-activated protein kinase (MAPK) family, and is known to have a pleiotropic role. Many studies have reported the involvement of Cot/Tpl2, mainly as a member of the Toll-like receptor (TLR) 4 signalling pathway in lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) production. At the same time, it is also related to the caspase-dependent apoptotic pathway. Thus, the role of Cot/Tpl2 in ischaemia/reperfusion injury (IRI) in which TNF-α and apoptosis are the major pathogenetic factors was studied. Methods: IRI was induced in wild type (Cot/Tpl2+/+) mice and in Cot/Tpl2-deficient (Cot/Tpl2-/-) mice. The extent of tubular injury and renal function were studied. TNF-α production, neutrophil infiltration and apoptosis were also compared between the two groups. Results: Cot/Tpl2-/- mice had preserved renal function compared with wild type mice in IRI. Although Cot/Tpl2 was phosphorylated in IRI and in the cultured tubular epithelial cells (TEC) after stimulation with LPS and hydrogen peroxide, there were no significant differences in terms of TNF-α production, neutrophil infiltration or MAPK activation between Cot/Tpl2+/+ and Cot/Tpl2-/- mice. In contrast, Cot/Tpl2-/- mice showed obviously reduced terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling positive cells and cleaved caspase-3 positive cells. Furthermore, Cot/Tpl2-deficient TECs demonstrated significantly less caspase-3 activation after hydrogen peroxide stimulation with comparable caspase-9 activation to wild type TEC. Conclusion: 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.

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