Alteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis

Abstract

Dysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. 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. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) 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 induces 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 have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.

Latifolin enhances both survival and cardiomyocyte differentiation of bone marrow mesenchymal stem cells on rat myocardial infarction model

“…Activation of NF-κB produces a series of in ammatory cytokines, such as IL-6, IL-1β, IL-12, TNFa. In this in ammatory cytokines, IL-6 plays a central role in body defense by stimulating various cell populations and is an essential part of the in ammatory mediator network [39,40] . In recent years, HIF-1/ NF-κB is being increasingly recognized as a critical factor in the in ammatory response.…”

Retinoid Homeostasis and Beyond: How Retinol Binding Protein 4 Contributes to Health and Disease

“…Not unexpectedly, chronic kidney disease (CKD) can also increase RBP4 in the circulation [ 172 ]. Experimentally, a 5/6 nephrectomy in mice increased concentrations of retinol and RBP4 in blood, which promoted the expression of G protein-coupled receptor-68 in circulating monocytes [ 173 ]. Cardiac infiltration of these monocytes under CKD conditions may exacerbate inflammation and fibrosis of the heart.…”

Physiological relevance of proton-activated GPCRs

“…In addition, local inflammation and concomitant hypoxia are themselves additional factors causing local acidification [20]. Activation of proton-activated GPCRs has been implicated in the regulation of inflammatory processes that span from the infiltration of immune cells to their differentiation, proliferation, and activity [7,27,120,136,153]. The abundant expression of GPR4 in endothelial cells allows to mediate at least in part the pH-dependent activation of endothelial cells and subsequent immune cell invasion [58,92].…”