SEP-9: THE CARDIAC DYSFUNCTION CAUSED BY SEPSIS IN ANIMALS WITH CHRONIC KIDNEY DISEASE IS ATTENUATED BY INHIBITING IκB KINASE

• Published in: Shock (Augusta, Ga.) Vol. 44 Suppl 2; p. 16
• Main Authors: Chen, J, Kieswich, J, Chiazza, F, Gobbetti, T, Patel, N.S.A, Perretti, M, Collino, M, Yaqoob, M.M, Thiemermann, C
• Format: Journal Article
• Language: English
• Published: by the Shock Society 01-10-2015
• ISSN: 1073-2322; 1540-0514
• DOI: 10.1097/01.shk.0000472053.76243.1f

INTRODUCTION:Patients with chronic kidney disease (CKD) requiring dialysis have a higher risk of sepsis and a 100-fold higher mortality. The severity of cardiac dysfunction predicts mortality among septic patients. Here we investigated the roles of pre-existing CKD on the cardiac outcome in mice with sepsis, and whether inhibition of IκB kinase (IKK) reduces the cardiac dysfunction in these animals.
METHODS:Male C57BL/6 mice were subjected to 5/6th nephrectomy (SNX) for 8 weeks, and were further subjected to either low dose LPS (2 mg/kg) or cecum ligation and puncture (CLP) (fluid and antibiotics given at 6 h and 18 h). CKD mice underwent CLP received IKK inhibitor IKK 16 (1 mg/kg, 1h-post CLP).
RESULTS:SNX resulted in significant rises in urea and creatinine, and a small (P < 0.05) reduction in ejection fraction (EF) as assessed via echocardiography, as well as increases in the cardiac phosphorylation of IκBα, nuclear translocation of the NF-κB subunit p65, iNOS expression, and phosphorylation of Akt and ERK1/2. When subjected to LPS or CLP, CKD mice exhibited exacerbation of cardiac dysfunction (Fig. A), increased lung inflammation and plasma cytokine levels (TNF-α, IL-1β, IL-6, IL-10) as well as further increased phosphorylation of IκBα, nuclear translocation of p65 and iNOS expression (heart). IKK 16 attenuated cardiac dysfunction (Fig. B), systemic inflammation and cardiac activation of NF-κB in CKD mice underwent CLP.
CONCLUSION:Pre-existing CKD aggravates the cardiac dysfunction caused by LPS or CLP in mice; this may (at least in part) be due to increased cardiac activation of NF-κB and iNOS expression.(Figure is included in full-text article.)