Downregulated expression of hepatic β-Klotho is associated with the hypertensive phenotype in SHR

Abstract

BackgroundFibroblast Growth Factor 21 (FGF-21) is an endocrine hormone that regulates metabolism and exerts cardiovascular effects through interaction with its co-receptor {beta}-Klotho (KLB). Impaired FGF-21/KLB signaling has been linked to metabolic disorders, but its role in hypertension remains unclear. ObjectiveThis study investigated the expression of genes related to the FGF-21 signaling axis (FGF-21, FGFR1, and KLB) in the liver and central nervous system (CNS) of spontaneously hypertensive rats (SHR) at pre-hypertensive (21 days) and hypertensive (90 days) stages. MethodsSystolic tail pressure (STP) and heart rate (HR) were recorded by tail-cuff plethysmography. Gene expression in the liver, brainstem, hypothalamus, and frontal cortex was quantified by RT-qPCR and normalized to {beta}-actin. ResultsSHR-90d exhibited significantly higher STP compared to SHR-21d, with no difference in HR. Hepatic KLB mRNA expression was markedly reduced in SHR-90d compared to SHR-21d (p < 0.05), while FGF-21 and FGFR1 levels remained unchanged. No significant alterations in FGF-21 pathway genes were detected in CNS regions. ConclusionThe selective downregulation of hepatic {beta}-Klotho in hypertensive SHR suggests a state of peripheral FGF-21 resistance, potentially linking metabolic dysregulation to the maintenance of hypertension. These findings highlight the liver as a peripheral site coupling metabolic dysfunction with neurogenic mechanisms of blood pressure control. Key findingsO_LIThe FGF-21/{beta}-Klotho axis remains unchanged in the CNS of SHRs. C_LIO_LIHepatic {beta}-Klotho is significantly reduced in hypertensive rats. C_LIO_LIThese findings suggest that a peripheral FGF-21 resistance may contribute to the metabolic and inflammatory milieu sustaining hypertension. C_LIO_LIThe study highlights the liver as a site linking metabolic dysfunction and neurogenic hypertension. C_LI