IkB 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 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.