Peroxisome Proliferator-Activated Receptor α Modulator Pemafibrate Ameliorates Salt-Sensitive Hypertension and Hypertensive Organ Damage After Ischemia-Reperfusion Injury in Rats

Background: Salt-sensitive hypertension develops following ischemia–reperfusion injury (IRI) in rats, with distal nephron sodium transporters playing a key role in the pathogenesis. We investigated the effects of peroxisome proliferator-activated receptor alpha (PPARα) activation by pemafibrate on IRI-induced salt-sensitive hypertension and hypertensive renal injury. Methods: Sprague-Dawley rats underwent right nephrectomy, followed 14 days later by transient left renal artery clamping to induce IRI. Rats were then provided 1.0% NaCl in drinking water (IRI/NaCl) to promote salt-sensitive hypertension. Pemafibrate (0.3 mg/kg), a selective PPARα modulator, was administered via chow beginning 3 weeks prior to IRI induction. Renal tissue and blood pressure were evaluated. Results: Pemafibrate upregulated PPARα expression in kidney tissue and significantly reduced blood pressure in IRI/NaCl rats. The expression of phosphorylated NCC, a sodium transporter in the distal nephron, was notably suppressed. Pemafibrate also reduced tubular injury and renal fibrosis, as evidenced by decreased fibrotic area on histology. Immunohistochemistry revealed attenuated deposition of α-SMA and collagen I, and reduced infiltration of CD68 positive macrophages. Furthermore, Western blot analysis showed inhibition of NLRP3 inflammasome activation, caspase-1 cleavage, and IL-1β expression in pemafibrate-treated rats. In addition, pemafibrate treatment led to preservation of renal morphology compared to controls. Gene expression analysis revealed downregulation of inflammatory and fibrotic mediators. Notably, nuclear translocation of PPARα was enhanced in tubular epithelial cells, consistent with transcriptional activation. Taken together, these findings demonstrate that pemafibrate confers renoprotection through anti-inflammatory, anti-fibrotic, and natriuretic mechanisms in the setting of IRI-induced salt-sensitive hypertension. Conclusion: Pemafibrate, a selective PPARα modulator, ameliorates salt-sensitive hypertension and hypertensive kidney injury after IRI in rats by suppressing NLRP3-mediated inflammation and inhibiting NCC activation. These findings suggest pemafibrate as a potential therapeutic agent for salt-sensitive hypertension and its associated organ damage.