P102 PH-SENSOR GPR68 PLAYS A ROLE IN THE CARDIOPROTECTIVE EFFECTS OF A HIGH FIBRE DIET

Background/Objective: Dietary fibre lowers blood pressure (BP) via short-chain fatty acids, acidic metabolites released from fibre fermentation by the bacteria in the large intestine. This acidic microenvironment may activate pH-sensing receptor GPR68, expressed primarily on immune cells, which play a crucial role in BP regulation. Here, we aimed to investigate whether GPR68 confers the cardioprotective effects of a high-fibre diet in hypertension by regulating inflammatory responses. Methods: 6–8-week-old male wildtype (WT) and GPR68-deficient (Gpr68-/-) fed a control or high-fibre diet underwent subcutaneous implantation of minipumps containing Angiotensin II (0.75 mg/kg body weight/day, 4 weeks, n=8/group). BP was measured weekly by tail-cuff. Morphometric, histological, and flow cytometric analyses were performed following the 4-week protocol. Results: High-fibre-fed WT mice exhibited blunted elevations in systolic BP (week 4; p=0.0508) and lower cardiac interstitial collagen deposition (p=0.0495) compared to WT mice fed a control diet. However, high fibre did not lower BP (week 4; control vs high-fibre, p=0.689) or cardiac collagen deposition (p=0.842) in Gpr68-/- mice. High-fibre-fed WT mice exhibited improved aortic elastin content compared to control-fed WT mice (p=0.0503), whereas this remained negligible in Gpr68-/- mice (p=0.885). Flow cytometric analysis revealed that high fibre decreased aortic macrophage (p=0.0072) and neutrophil cell counts (p=0.0273) in mice, irrespective of genotype. High fibre also decreased overall renal immune cell counts (p=0.0213) and dendritic cells (p=0.0488) in mice, irrespective of genotype. Finally, high fibre-fed mice had overall decreased circulating immune cell counts (p=0.0264), specifically CD8+ T cells (p=0.0235), and γδ T cells (p=0.0264). Conclusions: High fibre intervention on Angiotensin II-treated GPR68-deficient mice did not lower their BP or cardiac fibrosis. All angiotensin II-treated mice fed a high-fibre diet exhibited prominent changes in various immune cell populations, irrespective of genotype. Nonetheless, this study provides novel insight that GPR68 is involved in the cardioprotective effects of a high-fibre diet. This is most likely via in an immune-independent manner, warranting further investigations into its underlying mechanisms of action.