Role for clock protein PER1 in cardiac adaption to salt-sensitive hypertension in male rats

The clock protein PERIOD1 (PER1) is known to regulate the transcription of many genes, impacting subsequent physiological responses and working with other proteins to establish rhythmicity in processes such as blood pressure regulation. Global PER1 knock-out (KO) in male rats is associated with increased severity of the salt-sensitive (SS) hypertensive phenotype in Dahl SS rats. Male PER1 KO SS rats demonstrated reduced amplitude of heart rate as well as altered renal electrolyte and fluid balance with accompanying changes in the expression of relevant genes in the kidney. However, little is known regarding changes in gene expression in cardiac tissue which may contribute to this phenotype. The goal of this study was to test the hypothesis that knockout of PER1 in SS rats results in altered gene expression in the heart. We selected the following genes due to their role in the clock protein complex and circadian control over blood pressure: Basic Helix-Loop-Helix ARNT Like 1 ( Bmal1), Cryptochrome 1 and 2 ( Cry1, Cry2), and Period 2 ( Per2). Given its role in compensatory natriuretic responses to pressure overload, we also assessed the gene Nppa which encodes atrial natriuretic peptide (ANP). In order to test this hypothesis, hearts were collected at 2 am (during the rat active period) from male Dahl SS control and PER1 KO rats following 3 weeks of high salt (4% NaCl) diet (n=5-6). Changes in expression of candidate genes were measured using quantitative real time RT-PCR. Genotype effects were assessed using unpaired student’s t test. PER1 KO SS male rats on high salt diet exhibited significantly decreased cardiac expression of in the clock genes Bmal1 (p<0.0001), Cry1 (p=0.0007), and Cry2 (p=0.0094). Changes in Per2 expression were not apparent (p=0.1152). In contrast, PER1 KO rats exhibited significantly increased expression of Nppa (p=0.0017). Global PER1 knock-out in male SS rats results in hypertension associated with disrupted rhythms in heart rate. These changes are associated with reduction in expression of the genes encoding regulatory clock proteins Bmal1, Cry1, and Cry2, but not Per2. The decreased circadian gene expression in PER1 KO Dahl SS rats may contribute to the disrupted rhythms in heart rate. Increased ANP gene expression in the hearts of PER1 KO SS rats could serve as a compensatory mechanism to induce natriuresis. Thus, the data support the hypothesis that knockout of PER1 in SS rats alters gene expression in the heart. Together, these data illuminate a possible circadian-regulated pathway through which the heart and kidney communicate to respond to fluid and electrolyte imbalance in salt-sensitive hypertension. This work was supported by the National Institutes of Health grants R35 HL135789 (to AS), R01 DK109570 (to MLG and AS), R56DK128271 (to MLG), and Department of Veteran Affairs grants I01 BX004024 (to AS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.