In a mouse model of chronic kidney disease, mutation of the Clock gene or downregulation of monocytic GPR68 attenuated cardiac inflammation and fibrosis.
Does Clock gene mutation or GPR68 downregulation prevent CKD-induced cardiac inflammation and fibrosis in a 5/6 nephrectomy mouse model?
Monocytic expression of GPR68, driven by altered circadian clock machinery, is a key mediator of CKD-induced cardiac inflammation and fibrosis, presenting a potential novel therapeutic target.
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.
Yoshida et al. (Thu,) conducted a other in Chronic kidney disease-associated cardiac inflammation and fibrosis. Clock gene mutation (Clk/Clk) or GPR68 downregulation vs. Wild-type or control siRNA was evaluated on Cardiac inflammation and fibrosis. In a mouse model of chronic kidney disease, mutation of the Clock gene or downregulation of monocytic GPR68 attenuated cardiac inflammation and fibrosis.