Fenofibrate Ameliorates Salt-Sensitive Hypertension by Improving Renal Metabolic Homeostasis

Salt-sensitive hypertension (SSH) presents a formidable clinical challenge, given its intricate pathophysiology and a scarcity of targeted treatment options. This study investigates the therapeutic potential and underlying mechanisms of fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) activator, in SSH. Clinical observations indicate that SSH in male patients is often accompanied by dyslipidemia, with a positive correlation observed between blood pressure and lipid profiles—particularly triglycerides. In male Dahl salt-sensitive (SS) rats, a four-week oral administration of fenofibrate (100 mg/kg/day) prevented high-salt diet (HSD)-induced hypertension, dyslipidemia, and renal injury, without affecting body weight or food intake. Renal untargeted metabolomics demonstrated that HSD induced significant alterations in amino acid metabolism, the TCA cycle, pentose phosphate pathway, and arginine biosynthesis. Fenofibrate treatment reversed these metabolic abnormalities, notably restoring the levels of key amino acids such as arginine, serine, and branched-chain amino acids. Furthermore, fenofibrate stimulated the expression of renal PPARα and PPARγ. It potentiated nitric oxide (NO) synthesis by upregulating endothelial nitric oxide synthase (eNOS) protein expression and increasing arginine availability, improved the redox balance by enhancing antioxidant capacity, and elevated the cellular energy charge in the kidney. These findings demonstrate that fenofibrate ameliorates SSH by restoring renal metabolic homeostasis, enhancing NO synthesis, reducing oxidative stress, and improving bioenergetics, highlighting its promise as a therapeutic strategy for SSH, particularly in male patients with concurrent hyperlipidemia.