JUN Amino-Terminal Kinase 1 Signaling in the Proximal Tubule Causes Cell Death and Acute Renal Failure in Rat and Mouse Models of Renal Ischemia/Reperfusion Injury
Mulley, William R.
Davis, Roger J.
Flavell, Richard A.
Nikolic-Paterson, David J.
Ma, Frank Y.
Document TypeJournal Article
KeywordsAmino Acids, Peptides, and Proteins
Cellular and Molecular Physiology
Enzymes and Coenzymes
Female Urogenital Diseases and Pregnancy Complications
Male Urogenital Diseases
Pathological Conditions, Signs and Symptoms
MetadataShow full item record
AbstractActivation 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). There are two forms of JNK expressed in the kidney, JNK1 and JNK2. 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. Next, 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.
Grynberg K, Ozols E, Mulley WR, Davis RJ, Flavell RA, Nikolic-Paterson DJ, Ma FY. JUN Amino-Terminal Kinase 1 Signaling in the Proximal Tubule Causes Cell Death and Acute Renal Failure in Rat and Mouse Models of Renal Ischemia/Reperfusion Injury. Am J Pathol. 2021 Feb 16:S0002-9440(21)00049-3. doi: 10.1016/j.ajpath.2021.02.004. Epub ahead of print. PMID: 33607044. Link to article on publisher's site