NF-κB transcriptional inhibition ameliorates cisplatin-induced acute kidney injury (AKI).
2016
ABSTRACT The nuclear factor kappa-light-chain-enhancer of activated B cells (
NF-κB) cell signaling pathway is important in inflammation and cell survival. Inflammation and cell death in the kidney are features of
cisplatin-induced AKI. While it is known that
cisplatininduces
NF-κBsignaling in the kidney, the
NF-κBresponsive genes and the effect of direct
NF-κBtranscriptional inhibition in
cisplatin-induced AKI is not known. Mice injected with
cisplatin, 25 mg/kg, developed AKI,
acute tubular necrosis(ATN) and apoptosis on day 3. Mice were treated with JSH-23 (20 or 40 mg/kg) which directly affects
NF-κBtranscriptional activity. Kidney function, tubular injury (ATN, serum
neutrophil gelatinase-associated lipocalin[NGAL], but not apoptosis) and myeloperoxidase (MPO) activity were significantly improved by JSH-23 (40 mg/kg). Sixty one
NF-κBresponsive genes were increased by
cisplatinof which 21 genes were decreased by JSH-23. Genes that were decreased by JSH-23 that are known to play a role in
cisplatin-induced AKI were IL-10, IFN-γ, chemokine [C-C motif] ligand 2 (
CCL2) and
caspase-1. Another gene, caspase recruitment domain family, member 11 (
CARD11), not previously known to play a role in AKI, was increased more than 20-fold and completely inhibited by JSH-23.
CXCL1and TNF-α, known mediators of
cisplatin-induced AKI, were decreased by JSH-23.
RIPK1and 3, receptor-interacting serine/threonine-protein kinases, that play an important role in
necroptosis, were decreased by JSH-23. In mouse
proximal tubulecells in culture, JSH-23 resulted in an increase in apoptosis suggesting that the mechanism of protection against AKI by JSH-23 is not due to a direct effect on
proximal tubules. In conclusion,
NF-κBtranscriptional inhibition in
cisplatin-induced AKI ameliorates kidney function and ATN without a significant effect on apoptosis and is associated with a decrease pro-inflammatory mediators and
CARD11.
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