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.

• Authors: Yuya Yoshida, Naoya Matsunaga, Takaharu Nakao, Kengo Hamamura, Hideaki Kondo, Tomomi Ide, Hiroyuki Tsutsui, Akito Tsuruta, Masayuki Kurogi, Michio Nakaya, Hitoshi Kurose, Satoru Koyanagi, Shigehiro Ohdo
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 2783 (05 13 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33986294 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ARNTL Transcription Factors
• Arntl protein, mouse
• Cytokines
• GPR68 protein, mouse
• Receptors, G-Protein-Coupled
• CLOCK Proteins

Topics

• ARNTL Transcription Factors (metabolism)
• Animals
• CLOCK Proteins (genetics, metabolism)
• Cells, Cultured
• Circadian Clocks (genetics)
• Circadian Rhythm (genetics, physiology)
• Cytokines (biosynthesis)
• Fibrosis (pathology)
• Heart Diseases (pathology)
• Hypertension (genetics, pathology)
• Inflammation (genetics, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Mice, Transgenic
• Monocytes (metabolism)
• Receptors, G-Protein-Coupled (metabolism)
• Renal Insufficiency, Chronic (pathology)