Identification of Clock Genes Related to Hypertension in Kidney From Spontaneously Hypertensive Rats

Abstract

Background There is a diurnal variation in the blood pressure fluctuation of hypertension, and blood pressure fluctuation abnormality is considered to be an independent risk factor for organ damage including cardiovascular complications. In the current study, we tried to identify molecules responsible for blood pressure circadian rhythm formation under the control of the kidney biological clock in hypertension. Methods DNA microarray analysis was performed in kidneys from 5-week-old spontaneously hypertensive rats (SHRs)/Izm, stroke-prone SHR rats (SHRSP)/Izm, and Wistar Kyoto (WKY)/Izm rats. To detect variation, mouse tubular epithelial cells (TCMK-1) were stimulated with dexamethasone. We performed immunostaining and western blot analysis in the renal medulla of kidney from 5-week-old WKY rats and SHRs. Results We extracted 1,032 genes with E-box, a binding sequence for BMAL1 and CLOCK using a Gene Set Enrichment Analysis. In a microarray analysis, we identified 12 genes increased as more than 2-fold in the kidneys of SHRs and SHRSP in comparison to WKY rats. In a periodic regression analysis, phosphoribosyl pyrophosphate amidotransferase (Ppat) and fragile X mental retardation, autosomal homolog 1 (Fxr1) showed circadian rhythm. Immunocytochemistry revealed PPAT-positivity in nuclei and cytoplasm in the tubules, and FXR1-positivity in the cytoplasm of TCMK-1. In 5-week-old WKY rat and SHR kidneys, PPAT was localized in the nucleus and cytoplasm of the proximal and distal tubules, and FXR1 was localized to the cytoplasm of the proximal and distal tubules. Conclusions PPAT and FXR1 are pivotal molecules in the control of blood pressure circadian rhythm by the kidney in hypertension.

Circadian clock disruptions link oxidative stress and systemic inflammation to metabolic syndrome in obstructive sleep apnea patients

“…On the other hand, disrupted circadian clocks are also closely correlated with MetS components and glucose homeostasis. Recent in vivo studies indicate that peripheral clocks dysregulations in the liver, adipose, kidney, and smooth muscles are involved in the development of hypertension, diabetes, and obesity ( Chang et al, 2018 ; Nakashima et al, 2018 ; Hou et al, 2019 ; Murata et al, 2020 ; Pati et al, 2021 ). In Dec1-deficient mice models, expression of Atp1b1, a negative transcriptional target of Dec1 and anti‐phase regulator of blood pressure rhythm, was upregulated in the kidney, aorta, and heart tissues, and in turn reduced blood pressure ( Nakashima et al, 2018 ).…”

Circadian rhythms in thrombosis and atherothrombotic events

“…Finally, the nuclear factor E4BP4 repress DBP binding to D-box, inhibiting the expression of CCGs, forming the third stabilizing loop [39]. Deficiency or alteration of any of the components of the core circadian clock has an enormous impact at the vascular level, causing atherosclerosis [37][38][39] and risk of thrombosis [53], alteration of blood hemodynamics [43][44][45][46][47], promoting vascular injury [48], and contributes to aging [49][50][51][52]. It also alters liver function [40][41][42].…”

“…Deficiency in BMAL1 or PER2 is characterized by an increased vasoconstrictor response mediated by cyclooxygenase-1 (COX1) and reduced vasorelaxation mediated by decreases in NO and prostaglandin production [51,52]. All these factors increase the risk of hypertension in animal models [53]. The effects of BMAL1 deficiency are cell-type dependent; blood pressure rhythmicity is unaffected by deletion of Bmal1 in mouse cardiomyocytes, but is disrupted by deletion in vascular smooth muscle cells or endothelial cells [65].…”

Role of Circadian Transcription Factor Rev-Erb in Metabolism and Tissue Fibrosis

“…The authors reported that Rev-Erbα/β inhibition reduced folic-acid-induced inflammatory cytokine (TNFα, IL-1β) secretion, renal injury (KIM-1 and NGAL), and profibrotic (TGF-β, αMSA) gene expression [ 112 ]. Rev-Erbα expression was increased in the renal cortex and medulla of spontaneously hypertensive rats (SHRs) and stroke-prone SHR rats (SHRSP), compared to normal Wistar rats [ 202 ]. Dexamethasone administration to tubular epithelial cells of mice increased Rev-Erbα , Fragile X mental retardation autosomal homolog 1 ( Fxr1 ), and phosphoribosyl pyrophosphate amidotransferase ( Ppat ) expression [ 202 , 203 ].…”

“…Rev-Erbα expression was increased in the renal cortex and medulla of spontaneously hypertensive rats (SHRs) and stroke-prone SHR rats (SHRSP), compared to normal Wistar rats [ 202 ]. Dexamethasone administration to tubular epithelial cells of mice increased Rev-Erbα , Fragile X mental retardation autosomal homolog 1 ( Fxr1 ), and phosphoribosyl pyrophosphate amidotransferase ( Ppat ) expression [ 202 , 203 ]. Fxr1 and Ppat are involved in the formation of circadian rhythm in kidney tubules [ 202 ].…”