Arachidonic acid intake promotes hypertension and target-organ fibrosis through CYP4A-mediated 20-HETE overproduction: Integrated evidence from human and animal studies.

Individuals in the highest quartile of arachidonic acid intake had significantly higher odds of hypertension in NHANES cross-sectional analysis.

• OR = 1.262 (95% CI: 1.109–1.438, P < 0.001) for hypertension in the highest AA intake quartile.
• Data source was NHANES (National Health and Nutrition Examination Survey), a population-based cross-sectional dataset.
• Analysis was described as a cross-sectional design, limiting causal inference.

Two-sample Mendelian randomization confirmed causal effects of specific arachidonic acid metabolites on hypertension risk.

• Thromboxane was associated with hypertension risk (OR = 1.006, P < 0.001).
• Eicosanoid C20H28O4 was associated with hypertension risk (OR = 1.305, P = 0.009).
• 20-HETE-related C20H32O3 was associated with hypertension risk (OR = 1.290, P = 0.043).
• Mendelian randomization design was used to provide genetic, causal evidence beyond observational associations.

Single-cell transcriptomic profiling revealed increased renal expression of CYP4A11 in hypertensive patients.

• CYP4A11 is the human homolog of the rat CYP4A1 enzyme responsible for 20-HETE production.
• Increased CYP4A11 expression was identified specifically in renal tissue of hypertensive patients.
• This finding was interpreted as supporting a mechanistic link between AA metabolism via the CYP4A pathway and blood pressure regulation in humans.

High-dose dietary arachidonic acid elevated blood pressure in both Wistar-Kyoto (normotensive) and spontaneously hypertensive rats after six weeks.

• Both Wistar-Kyoto rats and spontaneously hypertensive rats (SHR) were used as animal models.
• Animals were fed a high-dose AA diet for six weeks.
• Significant elevations in systolic, diastolic, and mean arterial pressure were observed.
• Increased renal vascular resistance was also documented in AA-treated animals.

Arachidonic acid upregulated CYP4A1 expression and enhanced 20-HETE production without altering thromboxane synthase activity in animal models.

• CYP4A1 (rat homolog of human CYP4A11) expression was increased in AA-treated animals.
• 20-HETE production was enhanced as a consequence of CYP4A1 upregulation.
• Thromboxane synthase activity was not significantly altered by AA treatment, isolating CYP4A/20-HETE as the primary mechanistic pathway.
• These mechanistic analyses were conducted as part of in vivo experiments.

Histological assessments revealed glomerular edema, tubular injury, and marked cardiac and renal fibrosis in arachidonic acid-treated animals.

• Glomerular edema and tubular injury were observed in kidney tissue of AA-treated rats.
• Marked fibrosis was identified in both cardiac and renal tissues.
• These findings indicate that chronic high-dose AA intake causes multiorgan structural damage beyond blood pressure elevation.
• Histological assessments were performed after six weeks of high-dose AA dietary treatment.