SGLT2 inhibitor ameliorates hypertension by regulating the CYP4A/20-HETE pathway in the kidney

Sodium-glucose transport protein 2 inhibitors (SGLT2i), initially developed as antidiabetic agents and now established as foundational therapies for heart failure, have also shown antihypertensive effects in clinical trials involving patients with diabetes and heart failure. However, the underlying mechanisms remain incompletely understood. Given the diverse roles of arachidonic acid (AA) and its metabolites in blood pressure regulation, we investigated the antihypertensive effects of SGLT2i in hypertensive patients and an animal model and explored whether modulation of AA metabolism contributes to these effects. We first confirmed the antihypertensive effects of SGLT2i in a retrospective cohort study and spontaneously hypertensive rats (SHRs). Targeted metabolomic analysis of plasma and tissues from SHRs identified 20-hydroxyeicosatetraenoic acid (20-HETE) originating from the renal cortex as a key metabolite modulated by SGLT2i. Among the enzymes responsible for 20-HETE production, CYP4A but not CYP4F was found to be down-regulated by dapagliflozin at both mRNA and protein levels. Immunofluorescence colocalization further localized this effect to proximal tubular epithelial cells, where SGLT2i reduced CYP4A expression and subsequent 20-HETE production, leading to attenuated renal inflammation, fibrosis, and blood pressure elevation. Together, these findings not only confirm the antihypertensive effects of SGLT2i but also delineate a novel antihypertensive mechanism by which lower blood pressure, demonstrating that modulation of AA metabolism contributes partially to their blood pressure-lowering effects.