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

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9 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

All Science Journal Classification (ASJC) codes

  • Nephrology

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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, 13(5), 397-404. https://doi.org/10.1111/j.1440-1797.2008.00959.x