Loss of the clock protein PERIOD1 in salt-sensitive hypertension activates tissue-specific Angiotensinogen signaling in male rats

Background: Salt-sensitive (SS) hypertension (HTN) causes end-organ damage in the heart and kidney, driving cardiovascular disease, the leading cause of death in the US. Investigation of cardiac and renal coordination in HTN is necessary. One potential mechanism underlying this coordination is the molecular clock, which governs circadian physiology and functions in a tissue-specific manner. PERIOD1 (PER1) is a transcription factor and part of the core clock mechanism. Loss of PER1 drives HTN in pre-clinical models, and its expression is downregulated in the kidneys of human patients with HTN. Previously, we published that male Dahl SS PER1 knockout (KO) rats on a high-salt (HS) diet develop exacerbated HTN compared to control Dahl SS rats. This was associated with cardiac dysfunction, renal injury, and increased plasma aldosterone (aldo). Qiagen Ingenuity Pathway Analysis (IPA) of differentially expressed genes (DEGs) identified through bulk RNA sequencing (RNASeq) revealed that Angiotensinogen ( Agt ) is a key upstream regulator of DEGs in the kidney of male KO rats and acts through aldo. However, the mechanism network in the heart versus the kidney of male KO rats is unknown. Hypothesis: To investigate the role of PER1 in cardiac and renal coordination in HTN, this study aimed to identify PER1-dependent mechanism networks in the hearts of Dahl SS rats and compare IPA results between the heart and kidney. The goal of this study was to perform hypothesis-generating unbiased transcriptomics to further understand cardiorenal coordination in HTN. Furthermore, since aldo production is increased in male KO rats and aldo was identified in the IPA kidney mechanism network, we wanted to determine whether the expression of its receptor, the mineralocorticoid receptor (MR), is changed in the heart and the kidney. Methods: Hearts and kidneys were collected at 2 AM (during the rat active period) from male Dahl SS and KO rats following 3 weeks of HS (4% NaCl) diet (N=5-6). DEGs were determined from bulk RNASeq. Upstream regulators were identified using Qiagen IPA and compared to results in the kidney. MR protein expression was determined by Western blotting followed by densitometry analysis. Results: Similar to the findings in the kidney, IPA identified Agt as a key upstream regulator in the hearts of male KO rats on HS diet compared to Dahl SS controls (p=1.99E-32). In contrast to the kidney, aldo was not identified as a primary regulator whitin the Agt mechanism network in the heart. Instead, the network highlighted genes associated with the regulation of cardiac remodeling. MR protein expression is significantly increased in the kidney (p=0.0019; fold change= 2.11) but decreased in the heart (p=0.0158; fold change= -0.50) of male KO rats versus SS rats. Conclusions: Though Agt is the most likely upstream regulator of DEGs in both the heart and kidney of male KO rats, the downstream regulators involved in the predicted mechanism network are tissue-specific. MR protein expression is changed in male KO rats in a tissue-specific manner. This supports the hypothesis that loss of PER1 induces cardiac and renal dysfunction in SS HTN through diverging mechanisms. Future studies will determine the contribution of MR to this phenotype through the use of an MR antagonist. NIH/NIDDK 1R01DK109570-01A1 (to MLG), AHA 19EIA34660135 (to MLG), Florida Education Fund McKnight Fellowship (to SAE). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.