Oxysterol Sensing through GPR183 Triggers Endothelial Senescence and Cardio-renal Injuries via Altering Circadian Signaling in Hypertension

Background: Despite endothelial dysfunction being considered as the initial step of the development of hypertension and associated cardio-renal syndromes, effective therapeutic strategies to prevent endothelial injuries are still lacking. GPR183 is a recently identified GPCR for oxysterols and hydroxylated metabolites of cholesterol. Here, we explored a previously unappreciated role of GPR183 in hypertension and age-related cardio-renal injuries. Methods and results: Mice were treated with DOCA/Salt or AngII to induce hypertension. we found that endothelial GPR183 was significantly induced in aged or hypertensive mice, which was further confirmed in renal biopsies from elderly people or subjects with hypertensive nephropathy. In addition, we found that endothelial-specific GPR183 deletion markedly ameliorated endothelial senescence and cardio-renal injuries in hypertensive mice. Mechanistically, we found that GPR183 disrupted circadian signaling by inhibiting PER1 expression, thereby facilitating endothelial senescence and dysfunction through the cAMP/PKA/CREB signaling pathway. Importantly, pharmacological inhibition of the oxysterol-GPR183 axis by NIBR189 or Clotrimazole ameliorated endothelial senescence and cardio-renal injuries in hypertensive mice. Conclusions: GPR183 is an attractive therapeutic target for hypertension and age-related diseases. Targeting GPR183 could provide novel strategies for managing hypertension and its associated cardio-renal injuries. The gene expression of 2 samples from the DOCA mice was compared to 2 sham samples by RNA sequencing. The gene expression of 3 samples from the 24M mice was compared to 3 3M samples by RNA sequencing. The gene expression of 1 sample from the Aged person was compared to 1 Young samples by RNA sequencing. The gene expression of 3 sample from the KO GPR183 mice was compared to 3 WT samples by RNA sequencing.