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Updated: Jul 4, 2026
Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration
Published on: June 7, 2014
Serine/threonine kinase, Cot/Tpl2, regulates renal cell apoptosis in ischaemia/reperfusion injury
Takaaki Yaomura1, Naotake Tsuboi, Yoshinori Urahama
1Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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-alpha (TNF-alpha) 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-alpha 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-alpha 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-alpha 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.
Insights
Cot/Tpl2 deficiency preserves renal function during ischemia/reperfusion injury (IRI) by reducing apoptosis, not affecting TNF-alpha production. This suggests Cot/Tpl2 is a key promoter of apoptosis in IRI and a potential therapeutic target.
Area of Science:
- Biochemistry
- Immunology
- Nephrology
Background:
- Cot/Tpl2 is a serine/threonine protein kinase in the MAPK family.
- It plays a role in Toll-like receptor 4 (TLR4) signaling and lipopolysaccharide (LPS)-induced TNF-alpha production.
- Cot/Tpl2 is also implicated in caspase-dependent apoptosis.
Purpose of the Study:
- To investigate the role of Cot/Tpl2 in ischemia/reperfusion injury (IRI).
- To determine if Cot/Tpl2 influences TNF-alpha production and apoptosis in IRI.
- To evaluate Cot/Tpl2 as a potential therapeutic target for IRI.
Main Methods:
- IRI was induced in wild-type and Cot/Tpl2-deficient mice.
- Renal function, tubular injury, TNF-alpha production, neutrophil infiltration, and apoptosis were assessed.
- Cot/Tpl2 phosphorylation and caspase activation in tubular epithelial cells (TECs) were analyzed.
Main Results:
- Cot/Tpl2-deficient mice exhibited preserved renal function post-IRI compared to wild-type.
- No significant differences in TNF-alpha production or neutrophil infiltration were observed between groups.
- Cot/Tpl2 deficiency markedly reduced apoptosis markers (TUNEL, cleaved caspase-3) and caspase-3 activation in TECs.
Conclusions:
- Cot/Tpl2 acts as a promoter of apoptosis in IRI, rather than a member of the MAPK pathway in this context.
- Targeting Cot/Tpl2 may offer a therapeutic strategy for mitigating IRI.
- Further research into Cot/Tpl2's role in apoptosis is warranted.
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