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Alteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis.
- Source :
-
Nature communications [Nat Commun] 2021 May 13; Vol. 12 (1), pp. 2783. Date of Electronic Publication: 2021 May 13. - Publication Year :
- 2021
-
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.
- Subjects :
- ARNTL Transcription Factors metabolism
Animals
CLOCK Proteins metabolism
Cells, Cultured
Circadian Rhythm genetics
Cytokines biosynthesis
Fibrosis pathology
Hypertension genetics
Hypertension pathology
Inflammation genetics
Inflammation pathology
Male
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Transgenic
Receptors, G-Protein-Coupled metabolism
CLOCK Proteins genetics
Circadian Clocks genetics
Circadian Rhythm physiology
Heart Diseases pathology
Monocytes metabolism
Renal Insufficiency, Chronic pathology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33986294
- Full Text :
- https://doi.org/10.1038/s41467-021-23050-x