単球の概日時計変容と心不全増悪 ～新たな心腎連関の解明～

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  • The Relationship Between Heart Failure And Alteration of Circadian Clock in Monocyte : A Novel Cardio-renal Interaction

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<p>Dysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. Particularly, the CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. In this study, we analyzed the relationship between heart failure and Clock in 5/6 nephrectomy (5/6Nx) mice, which induce heart failure by chronic kidney disease (CKD). Surprisingly, cardiac inflammation and fibrosis were attenuated in Clock mutant (Clk/Clk) 5/6Nx mice even though they had high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induced the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes had increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbated inflammation and fibrosis of heart. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.</p>

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