NF-κB transcriptional inhibition ameliorates cisplatin-induced acute kidney injury (AKI).

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 cisplatin induces NF-κB signaling in the kidney, the NF-κB responsive genes and the effect of direct NF-κB transcriptional inhibition in cisplatin-induced AKI is not known. Mice injected with cisplatin, 25mg/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-κB transcriptional 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-κB responsive genes were increased by cisplatin of 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. CXCL1 and TNF-α, known mediators of cisplatin-induced AKI, were decreased by JSH-23. RIPK1 and 3, receptor-interacting serine/threonine-protein kinases, that play an important role in necroptosis, were decreased by JSH-23. In mouse proximal tubule cells 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-κB transcriptional 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.

• Authors: Abdullah Ozkok, Kameswaran Ravichandran, Qian Wang, Danica Ljubanovic, Charles L Edelstein
• Journal: Toxicology letters (Toxicol Lett) Vol. 240 Issue 1 Pg. 105-13 (Jan 05 2016) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 26546572 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015. Published by Elsevier Ireland Ltd.

Chemical References

• 4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine
• Acute-Phase Proteins
• CARD Signaling Adaptor Proteins
• Card11 protein, mouse
• Chemokine CXCL1
• Cxcl1 protein, mouse
• Interleukin-1
• Interleukin-6
• Lipocalin-2
• Lipocalins
• NF-kappa B
• Oncogene Proteins
• Phenylenediamines
• Tumor Necrosis Factor-alpha
• Lcn2 protein, mouse
• Creatinine
• Peroxidase
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk1 protein, mouse
• Ripk3 protein, mouse
• Caspase 1
• Cisplatin

Topics

• Acute-Phase Proteins
• Animals
• Apoptosis (drug effects)
• Blood Urea Nitrogen
• CARD Signaling Adaptor Proteins (genetics, metabolism)
• Caspase 1 (genetics, metabolism)
• Cells, Cultured
• Chemokine CXCL1 (blood)
• Cisplatin (administration & dosage, adverse effects)
• Creatinine (blood)
• Dose-Response Relationship, Drug
• Interleukin-1 (blood)
• Interleukin-6 (blood)
• Kidney Tubular Necrosis, Acute (chemically induced, drug therapy)
• Kidney Tubules, Proximal (cytology, drug effects, metabolism)
• Lipocalin-2
• Lipocalins (blood)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Oncogene Proteins (blood)
• Peroxidase (metabolism)
• Phenylenediamines (pharmacology)
• Receptor-Interacting Protein Serine-Threonine Kinases (genetics, metabolism)
• Signal Transduction
• Transcriptional Activation
• Tumor Necrosis Factor-alpha (blood)