Role of G protein-coupled receptor kinase-2 in peroxisome proliferator-activated receptor gamma-mediated modulation of blood pressure and renal vascular reactivity in SHR

Abstract

Background: Peroxisome proliferator-activated receptor γ (PPARγ), a nuclear transcription factor, modulates the expression/activity of G protein-coupled receptors (GPCRs), but its role in GPCR signaling is not clear. Increased GPCR kinase-2 (GRK-2) activity and receptor desensitization have been reported in hypertension. Method: In this study we investigated the role of GRK-2 in PPARγ-mediated blood pressure regulation in hypertension. SHR or WKY rats were treated with GW1929, a selective PPARγ ligand (0.5 mg/kg/day), or vehicle for 2 months. Systolic blood pressure (tail cuff plethysmography), whole kidney perfusion (laser scanner) and renal vascular reactivity (isolated perfused kidney) was determined. Results: GW1929 significantly reduced blood pressure (20 ± 1%) and increased renal perfusion (61 ± 3%) in SHR compared to WKY rats. Vasoconstriction to phenylephrine (100 μg) in the isolated perfused kidney was greater in SHRs (29 ± 1%) compared to WKY rats and this was abolished by GW1929. GW1929 enhanced acetylcholine-induced (30-300 μg) and sodium nitroprusside-induced vasodilatation in SHR by 46 ± 2% (p < 0.05) and 33 ± 2% (p < 0.05), respectively. Isoprenalin-induced (5-30 μg) vasodilatation was 43 ± 2% lower in SHR compared to WKY and GW1929 enhanced this vasodilatation by 55 ± 2%. In SHR kidney, GW1929 enhanced expression of PPARγ mRNA (34 ± 1%) but reduced that of GRK-2 (31 ± 3%). Conclusion: We suggest that downregulation of PPARγ but upregulation of GRK-2 increases blood pressure and impaired renal vascular reactivity in SHR and that PPARγ-mediated improvement in hypertension may involve transcriptional regulation of GRK-2 function. © 2009 S. Karger AG, Basel.