Role of G‐protein coupled receptor kinase‐2 (GRK2) in the modulation of renal vascular response in SHR by PPAR

Abstract

G‐protein coupled receptor (GPCR) kinase‐2 (GRK‐2) has been impllicated in hypertension and GRK‐2 inhibition reduced blood pressure (BP). Peroxisome proliferators activated receptor γ (PPARγ), a transcription factor regulates GPCRs but the connection with GRK‐2 is not known. Here, we examined GRK‐2 role in PPARγ‐mediated improvement in SHR. SHR/WKY rats were treated with GW1929 (GW), a PPARγ ligand (0.5mg/kg; 2 month) and BP was monitored. Whole kidney perfusion was determined (laser dopler scanner) and renal vascular response was measured with or without heparin, a GRK‐2 inhibitor. In SHR, GW reduced BP (25±1%) and increased renal perfusion (59±3%). Phenylephrine (PE) vasoconstriction was greater in SHRs (15±1%) then WKY rats and GW abolished this. Heparin attenuated PE response in untreated but not GW‐treated SHR. GW enhanced Ach vasodilatation in SHR (41±1%) and this was improved by heparin (79±18%). GW enhanced SNP vasodilatation in SHR (35±6%) but remained unchanged with heparin. In SHR, GW enhanced PPARγ mRNA but reduced GRK‐2 mRNA. These results suggest that down‐regulation of PPARγ and up‐regulation of GRK‐2 may responsible for increased renal vascular reactivity of SHR and that PPARγ transcriptionally attenuated GRK‐2 function in hypertension.