Renal inflammatory signaling alters cardiomyocyte kinetics and lead to HFpEF in CKD: A mechanistic proof of concept study.

Chronic kidney disease (CKD) carries a higher cardiovascular mortality and is a prominent risk factor for development of HFpEF. However, the pathophysiology of HFpEF in CKD has not been established. We have recently shown that experimental CKD-HFpEF is associated with increased renal release of inflammatory cytokines, particularly tumor necrosis factor (TNF)-α and interleukin (IL)-6, to the systemic circulation. Using a unique physiological biomimetic heart culture system, we test whether inflammatory cytokines of kidney origin contribute to the development of HFpEF in CKD. Pigs (4 each) were assigned to sham or CKD (bilateral renovascular disease and dyslipidemia) groups and followed for 14 weeks. Circulating levels of TNF-α and IL-6 were quantified (ELISA). In a biomimetic heart culture system, pig heart slices were exposed to plasma from normal or CKD pigs, or from normal pigs enriched with TNF-α and IL-6 (matching CKD concentration) with or without cytokine neutralizing antibodies (NA). Contractility and relaxation kinetics in vitro were determined in a dose/time dependent manner. CKD-HFpEF pigs exhibited elevated systemic levels of TNF-α and IL-6 (Figure 1A), associated with renal dysfunction, cardiac hypertrophy and fibrosis, and diastolic dysfunction. Plasma was collected from all animals. Then, pig heart slices were exposed to CKD-HFpEF, normal, or normal plasma enriched with cytokines, showing impaired contractility and speed of relaxation that improved after TNF-α and IL-6 neutralization (Figure 1B). Our observations implicate circulating inflammatory mediators released by dysfunctional kidneys in imposing damage to the remote myocardium, supporting a role of inflammatory cytokines of renal origin in renal-cardio pathophysiology in CKD-HFpEF. © FASEB.

Citation

Alejandro R Chade, Tamer M Mohamed, Alfonso Eirin. Renal inflammatory signaling alters cardiomyocyte kinetics and lead to HFpEF in CKD: A mechanistic proof of concept study. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2022 May;36 Suppl 1

PMID: 35553153

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