FGF21-NR1D1 Signaling Restrains the CYP4A/20-HETE/GPR75 Axis to Counteract Integrated Renal-Vascular Injury in Hypertension

Hypertension leads to concomitant injuries in the kidney and vasculature, yet the molecular mechanisms underlying this coordinated pathology remain incompletely understood. Here, we identify activation of the CYP4A/20-HETE/GPR75 axis as being associated with coordinated renal and vascular injury in hypertension. In hypertension, this pathway was concurrently activated in the liver, kidney, and vasculature and was associated with renal fibrosis, endothelial dysfunction, and oxidative stress. Pharmacological inhibition of CYP4A attenuated these pathological changes, supporting a functional contribution of this axis to hypertensive organ injury. Genetic and pharmacological evidence further demonstrated that FGF21 acts as an endogenous negative regulator of CYP4A/20-HETE signaling. Mechanistically, FGF21 restored expression of the nuclear receptor NR1D1, which was suppressed under hypertensive conditions, and this effect was associated with reduced CYP4A expression independently of ERK1/2 signaling. The functional relevance of the FGF21-NR1D1 axis was supported by the observation that NR1D1 antagonism largely abolished the protective effects of FGF21. Thus, these findings elucidate a mechanistic axis linking FGF21-NR1D1 signaling to the CYP4A/20-HETE/GPR75 pathway and suggest that modulation of this pathway may represent a potential therapeutic strategy for hypertensive renal and vascular injury.