title: IκB Kinase Inhibitor Attenuates Sepsis-Induced Cardiac Dysfunction in CKD.
abstract: Patients with CKD requiring dialysis have a higher risk of sepsis and a 100-fold higher mortality rate than the general population with sepsis. The severity of cardiac dysfunction predicts mortality in patients with sepsis. Here, we investigated the effect of preexisting CKD on cardiac function in mice with sepsis and whether inhibition of IκB kinase (IKK) reduces the cardiac dysfunction in CKD sepsis. Male C57BL/6 mice underwent 5/6 nephrectomy, and 8 weeks later, they were subjected to LPS (2 mg/kg) or sepsis by cecal ligation and puncture (CLP). Compared with sham operation, nephrectomy resulted in significant increases in urea and creatinine levels, a small (P<0.05) reduction in ejection fraction (echocardiography), and increases in the cardiac levels of phosphorylated IκBα, Akt, and extracellular signal-regulated kinase 1/2; nuclear translocation of the NF-κB subunit p65; and inducible nitric oxide synthase (iNOS) expression. When subjected to LPS or CLP, compared with sham-operated controls, CKD mice exhibited exacerbation of cardiac dysfunction and lung inflammation, greater increases in levels of plasma cytokines (TNF-α, IL-1β, IL-6, and IL-10), and greater increases in the cardiac levels of phosphorylated IKKα/β and IκBα, nuclear translocation of p65, and iNOS expression. Treatment of CKD mice with an IKK inhibitor (IKK 16; 1 mg/kg) 1 hour after CLP or LPS administration attenuated these effects. Thus, preexisting CKD aggravates the cardiac dysfunction caused by sepsis or endotoxemia in mice; this effect may be caused by increased cardiac NF-κB activation and iNOS expression.
authors.affiliation: Center for Translational Medicine and Therapeutics and.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Center for Translational Medicine and Therapeutics and.
authors.forename: Julius E
authors.initials: JE
authors.lastname: Kieswich
authors.affiliation: Department of Drug Science and Technology, University of Turin, Turin, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Chiazza
authors.affiliation: Center for Translational Medicine and Therapeutics and.
authors.forename: Amie J
authors.initials: AJ
authors.lastname: Moyes
authors.affiliation: Center for Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gobbetti
authors.affiliation: Center for Translational Medicine and Therapeutics and.
authors.forename: Gareth S D
authors.initials: GS
authors.lastname: Purvis
authors.affiliation: Central Laboratory Animal Facility, Leiden University Medical Center, Leiden, The Netherlands; and.
authors.forename: Daniela C F
authors.initials: DC
authors.lastname: Salvatori
authors.affiliation: Center for Translational Medicine and Therapeutics and.
authors.forename: Nimesh S A
authors.initials: NS
authors.lastname: Patel
authors.affiliation: Center for Biochemical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.affiliation: Center for Translational Medicine and Therapeutics and.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Hobbs
authors.affiliation: Department of Drug Science and Technology, University of Turin, Turin, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.affiliation: Center for Translational Medicine and Therapeutics and.|Department of Renal Medicine and Transplantation, Royal London Hospital, Whitechapel, London, United Kingdom.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Yaqoob
authors.affiliation: Center for Translational Medicine and Therapeutics and c.thiemermann@qmul.ac.uk.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D000818:Animals; D006331:Heart Diseases / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000201:enzymology*; D018805:Sepsis / Q000150:complications*
chemical_list: D051550:I-kappa B Kinase
keywords: cardiac dysfunction; chronic kidney disease; sepsis