Figure 1.

Schematic representation of the molecular components of the circadian timing system (A), and the status of circadian oscillation in the expression of clock genes and/or clock-controlled genes (CCGs) under physiological conditions (B) and in metabolic disorders and chronic kidney disease (CKD) (C). Under physiological conditions, the expression levels of the clock genes and/or CCGs undergo circadian oscillation in the central (suprachiasmatic nucleus [SCN] of the brain) and peripheral (e.g., heart, kidney, vasculature) clocks, mediated by transcriptional and translational feedback loops. The integral components of the core loop, CLOCK and BMAL1, form a heterodimer that induces E-box–mediated transcription of the negative regulators known as PERs and CRYs. Following accumulation of PER and CRY proteins, E-box–mediated transcription is repressed until cleared by proteasomal degradation. By contrast, in the regulatory or stabilizing loop, RORα and REV-ERBα modulate the BMAL1 mRNA levels by competitive actions on the REV-ERB/ROR–responsive element (RRE) residing in the BMAL1 promoter. All these components comprising the core and regulatory clocks determine the expression levels of core clock genes and/or CCGs via the E-box and/or RRE. Therefore, a rhythmic expression pattern is generated in physiological processes; regarding blood pressure (BP), for instance, this pattern is referred to as a dipping pattern. In subjects with metabolic dysfunction and CKD, however, loss of the circadian oscillation in the expression of core clock genes and/or CCGs leads to a disrupted dipping pattern of BP, which inevitably plays a critical role in the development of cardiovascular disorders. BMAL1: Brain and muscle arnt-like 1; CLOCK: Circadian locomotor output cycles kaput; CRYs: Cryptochromes; PERs: Periods; REV-ERVs: Nuclear receptors encoded by nuclear receptor subfamily 1, group D (NR1D); RORs: Retinoic acid receptor-related orphan receptors; RRE: REV-ERB/ROR responsive element; ZT: Zeitgeber time.