期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 191, 期 5, 页码 817-828出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2021.02.004
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资金
- National Health and Medical Research Council of Australia [1156982]
- Royal Australian College of Physicians Jacquot PhD Scholarship
- National Health and Medical Research Council of Australia [1156982] Funding Source: NHMRC
The JNK1 pathway plays a specific role in IRI-induced proximal tubule cell death, leading to acute renal failure. Jnk1 deficient mice and conditional Jnk1 deletion in the proximal tubule showed significant protection against acute renal ischemia/reperfusion injury. JNK2 does not have a similar role in this process.
Activation of the JUN amino-terminal kinase (JNK) pathway is prominent in most forms of acute and progressive tubulointerstitial damage, including acute renal ischemia/reperfusion injury (IRI). Two forms of JNK, JNK1 and JNK2, are expressed in the kidney. Systemic administration of pan-JNK inhibitors suppresses renal IRI; however, the contribution of JNK1 versus JNK2, and the specific role of JNK activation in the proximal tubule in IRI, remains unknown. These questions were addressed in rat and mouse models of acute bilateral renal IRI. Administration of the JNK inhibitor, CC-930, substantially reduced the severity of renal failure, tubular damage, and inflammation at 24 hours in a rat IRI model. Additionally, Jnk1?/? mice, but not Jnk2?/? mice, were shown to be significantly protected against acute renal failure, tubular damage, and inflammation in the IRI model. Furthermore, mice with conditional Jnk1 deletion in the proximal tubule also showed considerable protection from IRI-induced renal failure, tubular damage, and inflammation. Finally, primary cultures of Jnk1?/?, but not Jnk2?/?, tubular epithelial cells were protected from oxidant-induced cell death, in association with preventing phosphorylation of proteins (receptor interacting serine/threonine kinase 3 and mixed lineage kinase domain-like pseudokinase) in the necroptosis pathway. In conclusion, JNK1, but not JNK2, plays a specific role in IRI-induced cell death in the proximal tubule, leading to acute renal failure.
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