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JNK, a potential therapeutic target for the treatment of nephrotoxicity

Nephrotoxicity is a poisonous effect of some substances, including toxic chemicals and medication, on the kidneys, and cyclosporine A(CsA) nephrotoxicity is one kind of nephrotoxicity. It is reported that the epithelial to mesenchymal transition(EMT) is an important mechanism contributing to the pathogenesis of cyclosporine (CsA) nephrotoxicity by promoting the generation of myofibroblasts. Some studies suggested that he endoplasmic reticulum (ER) stress as a potential mechanism may participate in the modulation of tubular cell plasticity in CsA-induced EPCs[1]. However, the precise mechanisms have not been known.
     The signaling pathways that are mediated by c-jun N terminal kinase (JNK) have been reported to involved in many inflammatory responses in mammals and insects, and also can be  activated during ER stress following TRAF-2 recruitment and activation through Ire1 signaling[2].
     Accordingly, Pallet et al. explore the effects of JNK signaling on tubular EPCs following CsA exposure. First, HRECs that were exposed to CsA displays early JNK phosphorylation, suggesting that CsA activates the JNK signaling pathway. Moreover, the activation of JNK signaling by CsA regulates the phenotypic changes of HRECs, since the JNK inhibitor (L)-JNKI1 reduces the CsA-induced EPCs, increases cell viability, and inhibits CsA-induced E-cadherin downregulation. Snail-1, which suppresses the expression of E-cadherin, is consider as a central regulator of EMT, and the result indicates that  CsA can posttranscriptionally mediate Snail-1 protein expression in a JNK-dependent manner[3].
     Taken together, CsA can activate JNK signaling in tubular cells, resulting in epithelial phenotypic changes. Therefore, JNK may represent a potential therapeutic target for the treatment of nephrotoxicity.


References
[1]. American Journal of Transplantation, 2008:2283–2296.
[2]. Science, 2000; 287:664–666.
[3]. Journal of Transplantation, 2011; doi:10.1155/2012/348604.

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S1460 SP600125 SP600125 is a broad-spectrum JNK inhibitor for JNK1, JNK2 and JNK3 with IC50 of 40 nM, 40 nM and 90 nM in cell-free assays, respectively; 10-fold greater selectivity against MKK4, 25-fold greater selectivity against MKK3, MKK6, PKB, and PKCα, and 100-fold selectivity against ERK2, p38, Chk1, EGFR etc. (737) (6)
S2286 Cyclosporin A Cyclosporin A is an immunosuppressive agent, binds to the cyclophilin and then inhibits calcineurin with IC50 of 7 nM in a cell-free assay, widely used in organ transplantation to prevent rejection. (30) (3)

Related Targets

JNK