title: 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.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Ozkok
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Kameswaran
authors.initials: K
authors.lastname: Ravichandran
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pathology, University Hospital Dubrava, Zagreb, Croatia.
authors.forename: Danica
authors.initials: D
authors.lastname: Ljubanovic
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado, USA. Electronic address: Charles.edelstein@ucdenver.edu.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
mesh_terms: D000209:Acute-Phase Proteins; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001806:Blood Urea Nitrogen; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000097:blood; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects*; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000188:drug therapy*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000097:blood; D009195:Peroxidase / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: C549066:4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine; D000209:Acute-Phase Proteins; D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D007375:Interleukin-1; D015850:Interleukin-6; D000071068:Lipocalin-2; D054834:Lipocalins; D016328:NF-kappa B; D015513:Oncogene Proteins; D010655:Phenylenediamines; D014409:Tumor Necrosis Factor-alpha; C071332:Lcn2 protein, mouse; D003404:Creatinine; D009195:Peroxidase; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse; D020170:Caspase 1; D002945:Cisplatin
keywords: Acute kidney injury; Apoptosis; Cisplatin; NF-κB; Necrosis