Renal and Vascular Effects of Selective FGFR4 Inhibition in Folic Acid-induced Kidney Injury in Rats

Background/Aim: Fibroblast growth factor-23 (FGF-23) has been implicated in chronic kidney disease (CKD)-associated cardiovascular dysfunction, potentially through fibroblast growth factor receptor 4 (FGFR4). This study investigated renal and vascular alterations in folic acid-induced CKD and evaluated the effects of selective FGFR4 inhibition. Materials and Methods: Male Sprague-Dawley rats were assigned to healthy control, CKD control, vehicle, and roblitinib-treated groups. CKD was induced by a single intraperitoneal dose of folic acid. Serum creatinine, FGF-23, tumor necrosis factor-α, interleukin-1β, and asymmetric dimethylarginine levels were measured. Vascular reactivity was evaluated in isolated aortic rings using phenylephrine, carbachol, and sodium nitroprusside. Renal fibrosis, carotid calcification, and medial thickness were assessed histologically. Results: Folic acid administration increased serum creatinine and relative kidney weight and impaired both endothelium-dependent and endothelium-independent vascular relaxation. Relative kidney weight was lower in the roblitinib-treated group than in the CKD control group. However, changes in vascular responses observed in both the treatment and vehicle groups prevented these effects from being attributed specifically to FGFR4 inhibition. FGF-23 and inflammatory marker levels did not differ significantly among the groups. Carotid medial thickness was significantly greater in the treatment group than in the CKD-control group (p<0.05), whereas no other significant between-group differences were detected. Conclusion: Folic acid-induced renal injury was associated with early functional vascular impairment despite limited structural and inflammatory alterations. Selective FGFR4 inhibition did not demonstrate a clear therapeutic effect. Further in vivo studies using complementary CKD models, direct assessment of FGFR4 signaling, and vehicle formulations without intrinsic vascular activity are required to validate these findings.