Dietary Salt Impairs Circadian Physiological Metabolic Adaptations in Salt-Sensitive Hypertension

Mar 11, 2026Function (Oxford, England)

High Salt Intake Disrupts Daily Metabolic Adjustments in Salt-Sensitive High Blood Pressure

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Abstract

High salt intake in Dahl salt-sensitive rats is associated with disrupted diurnal patterns in kidney function.

Deletion of core clock proteins in SS rats worsens hypertension and kidney injury.
High salt diets reduce time-of-day-dependent changes in kidney gene expression.
Pathway analyses indicate significant stress and immune responses linked to high salt intake.
Remodeling of the pyruvate dehydrogenase complex is a key finding in both transcriptomic and phosphoproteomic analyses.
Renal genes show diurnal oscillations under normal conditions, which are severely disrupted in SS hypertension.

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The body's circadian rhythm is coordinated by core clock proteins (PER, CRY, CLOCK, and BMAL1) that function in both the central hypothalamic and peripheral tissue molecular clocks. Our recent study demonstrated that deletion ofin Dahl salt-sensitive (SS) rats (SS) exacerbated SS hypertension (HTN), kidney injury, and disrupted blood pressure rhythms. To define time-of-day-, genotype-, and diet-dependent alterations in the renal transcriptome and proteome associated with SS HTN, kidney cortex samples were collected from SS and SSrats fed either a normal salt (NS, 0.4% NaCl) or high salt (HS, 4% NaCl) diet, during both the active (night) and inactive (day) periods. Dietary challenges were conducted for 3 weeks in male rats. Bulk RNA-sequencing was performed on both NS and HS-fed groups, and proteomic analyses were performed in HS-fed groups. In SS rats, HS intake blunted time-of-day-dependent transcriptional changes. Pathway analyses predicted significant stress and immune responses, as well as metabolic adaptations, induced by the HS diet. Specifically, the remodeling of the pyruvate dehydrogenase complex was identified as a key prediction in both transcriptomic and phosphoproteomic datasets. As expected,deletion further exacerbated disruptions in immune regulation and metabolic adaptation. Collectively, these findings demonstrate that numerous renal genes exhibit diurnal oscillations under physiological conditions and are profoundly disrupted in SS HTN, likely contributing to impaired kidney function and circadian misalignment of blood pressure regulation. Per1Per1Per1-/-Per1-/-

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Dietary Salt Impairs Circadian Physiological Metabolic Adaptations in Salt-Sensitive Hypertension

Abstract

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