FC 064A RENAL-CARDIO INFLAMMATORY AXIS MEDIATES CARDIAC DYSFUNCTION IN CKD VIA IL-33-ST2: A NOVEL MECHANISM

Abstract

Abstract Background and Aims We developed a swine model of chronic kidney disease (CKD) that also display cardiac abnormalities associated with heart failure (HF). Inflammation contributes to progressive renal dysfunction and increases cardiovascular mortality of patients with CKD. Interleukin (IL)-33 is a tissue-derived nuclear cytokine from the IL family. IL-33 constitutively expressed but upregulated and released after cellular damage or necrotic cell death, acting as a pro-inflammatory cytokine. We hypothesize that IL-33 plays a prominent mechanistic role in renal-cardio pathophysiology in CKD. Method We induced CKD in 10 pigs via bilateral renovascular disease and dyslipidemia. We developed a renally-targeted biopolymer-fused peptide inhibitor of nuclear-factor kappa (NF-k)B (ELP-p50i) and show it blocks NFkB activity in vitro and in vivo. NF-kB is a key pro-inflammatory transcription factor upregulated in CKD and closely interacts with IL-33. Pigs were observed for 6 weeks, renal (multi-detector CT) and cardiac structure and function (echo) were quantified, then randomized to single intra-renal ELP-p50i or placebo (n=5 each), and studies repeated 8 weeks later. Blood was collected to measure circulating TNF-α, IL-33 and its specific decoy receptor soluble (s) ST2 (ELISA). Heart weights were measured after euthanasia, and renal and cardiac expression of ST2 and morphometric analyses were performed. Results Loss of renal function in CKD was accompanied by increased heart weight, left ventricular (LV) hypertrophy, diastolic dysfunction, abnormal LV strain, renal/cardiac fibrosis, circulating TNF-α, IL-33 but unchanged sST2, and increased renal/cardiac ST2 expression. Most of these changes were improved after intra-renal ELP-p50i and accompanied by augmented sST2, suggesting that inhibition of renal inflammation can attenuate cardiac abnormalities via augmented clearance of IL-33 (Figure). Conclusion Our study supports a prominent role for renal inflammation as a driving force for precursors of HF in CKD, proposing a renal-cardio inflammatory axis possibly mediated by NF-kB-TNF-α-IL-33/ST2 interactions. TNF-α can stimulate IL-33 as IL33 can activate NF-kB and TNF-α, extending this inflammatory loop in both the kidney and heart. We show that a translational renal anti-inflammatory strategy via targeted inhibition of renal NFkB inhibits this axis and improves renal and cardiac function, which may guide to new treatments targeting renal inflammation in CKD.