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

Background

Fibroblast Growth Factor 21 (FGF-21) is an endocrine hormone that regulates metabolism and exerts cardiovascular effects through interaction with its co-receptor β-Klotho (KLB). Impaired FGF-21/KLB signaling has been linked to metabolic disorders, but its role in hypertension remains unclear.

Objective

This 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.

Methods

Systolic 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 β-actin.

Results

SHR-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.

Conclusion

The selective downregulation of hepatic β-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 findings

• The FGF-21/β-Klotho axis remains unchanged in the CNS of SHRs.

• Hepatic β-Klotho is significantly reduced in hypertensive rats.

• These findings suggest that a peripheral FGF-21 resistance may contribute to the metabolic and inflammatory milieu sustaining hypertension.

• The study highlights the liver as a site linking metabolic dysfunction and neurogenic hypertension.