Table 3 Effects of GRK modification on blood pressure and related substrates
GRK isoform | GRK Modification | Mouse Phenotype | Regulation on Substrate and Its Functions |
|---|---|---|---|
GRK2 | VSM-targeted overexpression | Increases resting SBP, DBP and MAP [34]; increases SBP but not MAP or DBP [60] | Attenuates β-AR signaling and vasodilation, increases aortic medial VSM thickness, and causes cardiac hypertrophy [34]; impairs β-AR signaling in VSM [60] |
Global adult hemizygous mice (GRK2+/-) | No change in basal SBP, but reduced Ang II-induced hypertension | Increases aortic vasoconstrictor responses to phenylephrine and ET-1 but not to Ang II; increases endothelium-dependent vasodilator responses and NO release; prevents Ang II-induced vascular remodeling [31] | |
Global knockdown Grk2 using shRNA | Increases phenylephrine-induced hypertension and contractile response of mesenteric arteries and isoproterenol-mediated vasodilation in phenylephrine pre-constricted mesenteric arteries; decreases desensitization of β-AR signaling in VSMCs [33]; decreases kidney size, nephrogenesis and glomerular count, and glomerular filtration; increases RAS activity and renin- and AT1R-mediated ROS production; does not affect renal AT1R expression [43] | ||
GRK2ct or VSM-selective Grk2 ablation | no effect on basal blood pressure; does not prevent 2K1C hypertension [39] | Increases β-AR mediated dilation and α1D-AR stimulated vasoconstriction [39] | |
Selective deletion of endothelial Grk2 | not mentioned | Impairs α1-AR-, serotonin-, oxytocin-, and KCl-induced aortic vasoconstriction; increases aortic inflammation, degeneration, and mitochondrial ROS production [59] | |
Grk2 knockdown using siRNA | not mentioned | Improves insulin-induced vasodilation of mesenteric arteries in SHRs [58] | |
GRK3 | Cardiac-restricted expression of a peptide inhibitor of GRK3 in mice | Increases SBP, DBP, and cardiac output | Does not affect cardiac β-AR responsiveness; increases α1-AR but not β-AR -induced cardiac hypertrophy [73]; attenuates cardiac dysfunction and heart failure after chronic pressure overload [74] |
GRK4 | Global Grk4 knockout | Decreases SBP and DBP | Cardiac and renal function not studied [78] |
Renal depletion using As-Odns | Attenuates SBP and MAP in SHRs [79] | Decreases renal D1R phosphorylation, increases sodium excretion and urine volume, and reduces protein excretion in SHRs [79] | |
UTMD-targeted renal depletion of Grk in rodents | Reduces SBP [81] | Reduces the phosphorylation of some receptors expressed in the kidney (D1R, adipoR1, ETBR, AT2R) and improves receptor-mediated natriuresis and diuresis [21, 81, 82, 93] | |
Overexpression of human GRK4γ 142V in mice | Causes hypertension (normal-salt diet); increases systolic blood pressure in response to Ang II [77] | Impairs renal receptor (D1R, adipoR1, ETBR, AT2R and CCKBR)-mediated sodium excretion [15, 21, 81, 82, 93, 170]; increases arterial AT1R expression and -mediated vasoconstriction [77]; increases renal AT1R expression and -induced sodium retention [78] | |
Overexpression of human GRK4 γ 486V in mice | Salt-sensitive hypertension [83] | Impairs sodium excretion and increases renal oxidative stress [83]; increases renal AT1R expression and activity [83] | |
Overexpression of human GRK4 65L in mice | Salt-sensitive hypertension | Increases D1R phosphorylation [174], increases renal Na+,K+/ATPase and α-ENaC expressions [175] | |
GRK5 | VSM-specific Overexpression in mice | Causes hypertension; increases MAP to a greater extent in male than female mice | Increases norepinephrine-mediated vasoconstriction in male mice; Decreases βAR-mediated vasodilation and increases Ang II–stimulated vasoconstriction in female but not male mice [122] |
AdGRK5-NT in rats | Does not affect the blood pressures of WKY and SHRs [123] | Decreases cardiac mass in SHRs and prevents the development of phenylephrine-induced left cardiac hypertrophy, inhibits NF-κB signaling, transcriptional activity and cardiac fibrosis and apoptosis [123] | |
Global knockout mice | Not mentioned | Decreases insulin sensitivity [124] | |
GRK6 | Global knockout mice | Not mentioned | Causes striatal D2-like receptor supersensitivity [176] Increases ear inflammation [177] |
