TY - JOUR
T1 - IkB kinase inhibitor attenuates sepsis-induced cardiac dysfunction in CKD
AU - Chen, Jianmin
AU - Kieswich, Julius E.
AU - Chiazza, Fausto
AU - Moyes, Amie J.
AU - Gobbetti, Thomas
AU - Purvis, Gareth S.D.
AU - Salvatori, Daniela C.F.
AU - Patel, Nimesh S.A.
AU - Perretti, Mauro
AU - Hobbs, Adrian J.
AU - Collino, Massimo
AU - Yaqoob, Muhammad M.
AU - Thiemermann, Christoph
N1 - Publisher Copyright:
Copyright © 2016 by the American Society of Nephrology.
PY - 2017/1
Y1 - 2017/1
N2 - 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 IkBkinase (IKK) reduces the cardiacdysfunction inCKDsepsis.MaleC57BL/6mice underwent 5/6 nephrectomy, and 8weeks later, theywere subjected to LPS (2mg/kg)or sepsisby 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 IkBa, Akt, and extracellular signal-regulated kinase 1/2; nuclear translocation of the NF-kB subunit p65; and inducible nitric oxide synthase (iNOS) expression.When subjected to LPS or CLP, compared with sham-operatedcontrols,CKDmice exhibited exacerbation of cardiac dysfunction and lunginflammation, 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 IKKa/b and IkBa, 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.
AB - 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 IkBkinase (IKK) reduces the cardiacdysfunction inCKDsepsis.MaleC57BL/6mice underwent 5/6 nephrectomy, and 8weeks later, theywere subjected to LPS (2mg/kg)or sepsisby 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 IkBa, Akt, and extracellular signal-regulated kinase 1/2; nuclear translocation of the NF-kB subunit p65; and inducible nitric oxide synthase (iNOS) expression.When subjected to LPS or CLP, compared with sham-operatedcontrols,CKDmice exhibited exacerbation of cardiac dysfunction and lunginflammation, 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 IKKa/b and IkBa, 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.
UR - http://www.scopus.com/inward/record.url?scp=85012081909&partnerID=8YFLogxK
U2 - 10.1681/ASN.2015060670
DO - 10.1681/ASN.2015060670
M3 - Article
SN - 1046-6673
VL - 28
SP - 94
EP - 105
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
IS - 1
ER -