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.
BACKGROUND
Peroxisome proliferator-activated receptor gamma (PPARgamma), 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.


METHODS
In this study we investigated the role of GRK-2 in PPARgamma-mediated blood pressure regulation in hypertension. SHR or WKY rats were treated with GW1929, a selective PPARgamma 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 microg) 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 microg) and sodium nitroprusside-induced vasodilatation in SHR by 46 +/- 2% (p < 0.05) and 33 +/- 2% (p < 0.05), respectively. Isoprenalin-induced (5-30 microg) 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 PPARgamma mRNA (34 +/- 1%) but reduced that of GRK-2 (31 +/- 3%).


CONCLUSIONS
We suggest that downregulation of PPARgamma but upregulation of GRK-2 increases blood pressure and impaired renal vascular reactivity in SHR and that PPARgamma-mediated improvement in hypertension may involve transcriptional regulation of GRK-2 function.
Yousefipour
Zivar
Z
Center for Cardiovascular Diseases, Texas Southern University, Houston, Texas, USA.
Oyekan
Adebayo
A
Newaz
Mohammad
M
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000502:physiology*; D006973:Hypertension / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D047495:PPAR gamma / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR
D047495:PPAR gamma; C496569:Grk2 protein, rat; D054769:G-Protein-Coupled Receptor Kinase 2