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. Author manuscript; available in PMC: 2022 Dec 7.
Published in final edited form as: Pharmacol Ther. 2022 Apr 27;239:108194. doi: 10.1016/j.pharmthera.2022.108194

Table 2.

In vivo and in vitro studies of GRK4 modification or variants.

GRK4 modification or variants Animal or cell Type of GRK4 modification Effects of GRK4 modification on blood pressure and related functions References
In vivo studies of GRK4 modification or variants
GRK4 knockout Knockout mice Global knock mice Decreases systolic and diastolic blood pressures Wang et al., 2016
GRK4 siRNA SHRs Silencing renal GRK4 expression via UTMD-delivered GRK4 siRNA Decreases blood pressure; increases sodium excretion and urine volume, reduces D1R phosphorylation and improves D1R-mediated sodium excretion; restores the adiponectin- or ETBR-mediated increase in sodium excretion Huang et al., 2016; Yang et al., 2020; Zhang et al., 2020
GRK4 As-Odns SHRs and WKY rats Renal GRK4 depletion via the chronic renal cortical interstitial infusion of GRK4 As-Odns Decreases D1R phosphorylation to a greater extent in SHRs than in WKY rats; increases sodium excretion and urine volume, attenuates the increase in arterial blood pressure with age, and decreases protein excretion in SHRs, but not WKY rats Sanada et al., 2006; Yatabe et al., 2008
GRK4 and AT1R As-Odns SHRs and WKY rats Silencing both renal GRK4 and AT1R via intrarenal cortical infusion of both GRK4 and AT1R As-Odns Decreases blood pressure and increases sodium excretion to a greater extent in SHRs than WKY rats; decreases circulating levels of renin, ang II, and aldosterone, reduces urine protein excretion and improves the GSI in SHRs and WKY rats; greater natriuresis and amelioration of hypertension in SHRs than the rats treated with either GRK4 or AT1R As-Odn Yatabe et al., 2008
Overexpression of hGRK4γ142V hGRK4γ WT and hGRK4γ 142 V transgenic mice Global transgenic mice Higher blood pressure and renal D1R phosphorylation, impaired D1R-mediated sodium excretion, increased renal AT1R expression and pressor response to Ang II in hGRK4γ 142 V transgenic mice than those in hGRK4γ WT transgenic mice; higher AT1R protein expression in the aorta of GRK4γ 142 V transgenic mice than hGRK4γ WT transgenic mice; hyperphosphorylation of renal ETBR and AdipoR1, impairment of ETBR or AdipoR1 function, less natriuresis and diuresis induced by endothelin or adiponectin in SHRs than WKY rats and GRK4γ 142 V transgenic mice than hGRK4γ WT transgenic mice Felder et al., 2002; Yang et al., 2020; Wang et al., 2016; Wang et al., 2007; Zhang et al., 2020.
Overexpression of hGRK4γ 486 V hGRK4γ WT and hGRK4γ 486 V transgenic mice Global transgenic mice Impairs sodium excretion, increases renal oxidative stress, and increases blood pressure with high salt diet in hGRK4γ 486 V transgenic mice, relative to hGRK4γWT transgenic mice Diao et al., 2017; Wang et al., 2006
Overexpression of hGRK4γ 65 L hGRK4γ WT and hGRK4γ 65 L transgenic mice Global transgenic mice Increases blood pressure with high salt diet in hGRK4γ 65 L transgenic mice, relative to hGRK4γ WT transgenic mice Asico and Jose, unpublished data
In vitro studies of GRK4 modification or variants
Inhibition of GRK4 activity RPT cells from normotensive humans Treatment with heparin, an inhibitor of GRK activity Decreases the expression of GRK2 and GRK4 and attenuates the desensitization of D1R, blunts p44/42 phosphorylation and mitogenesis induced by D3R stimulation in hRPTCs Watanabe et al., 2002; Villar et al., 2009
Inhibition of GRK4 expression RPT cells from hypertensive humans Treatment with antibody recognizing GRK4γ/δ isoforms Blocks the stimulatory effect of the D1-like receptor agonist, fenoldopam, on GRK activity Felder et al., 2002
GRK4 As-Odns RPT cells from hypertensive humans GRK4 knockdown with its specific As-Odns Blocks the D1R phosphorylation, blunts fenoldopam-induced D1R desensitization, and restores the D1-like receptor-mediated cAMP production Felder et al., 2002
GRK4 siRNA RPT cells from SHRs GRK4 knockdown with its specific siRNA Recovers the impaired inhibitory effect of ETBR on Na+/K+-ATPase activity Yang et al., 2020
GRK4 siRNA RPT cells from normotensive humans RPT cells transfected with GRK4 siRNA Blunts the D3R-mediated mitogenesis Villar et al., 2009
Inhibition of GRK4 activity Rat intestinal epithelial cells Treatment with heparin, an inhibitor of GRK activity Heparin prevents the loss of inhibition of NHE activity caused by 25 min exposure to SKF-38393, a D1-like receptor agonist Fraga et al., 2004
Inhibition of GRK4 expression Rat intestinal epithelial cells Treatment with the anti-GRK4–6 antibody Restores the loss of inhibition of NHE activity and stimulation of AC activity caused by 25 min exposure to SKF-38393, a D1-like agonist Fraga et al., 2004
Overexpression of GRK4 variants CHO cells Transfected with GRK4γ with SNPs (A142V, R65L, A486V or combined R65L and A486V) Increases basal D1R phosphorylation and impairs D1R-mediated cAMP accumulation Felder et al., 2002
Overexpression of GRK4 splice variants CHO cells Transfected with GRK4α, GRK4β, GRK4γ or GRK4δ GRK4γ and GRK4α increase the phosphorylation of D3R compared with untreated control cells; activation of D3R results in a 3-fold and 2-fold increase in D3R phosphorylation in cells expressing GRK4γ and GRK4α, respectively Villar et al., 2009
Overexpression of hGRK4γ 142 V RPT cells from normotensive humans RPT cells transfected with hGRK4γ 142 V and GRK4γ WT plasmids Increases activity of Agtr1 and AT1R protein expression Wang et al., 2016
Overexpression of hGRK4γ 142 V VSMCs Transfected with hGRK4γ 142 V and GRK4γ WT plasmids Higher AT1R protein and mRNA expressions, lower AT1R phosphorylation and protein degradation, higher AT1R-mediated intracellular calcium concentration after stimulation with Ang II in hGRK4γ 142 V than in GRK4γ WT cells Chen et al., 2014
Overexpression of GRK4 HEK293 cells Transfected with full-length GRK4 plasmid Induces cellular senescence, halts cell proliferation Xiao et al., 2017; Luo et al., 2019

Abbreviations: AC, adenylyl cyclase; AdipoR1, adiponectin receptor 1; Ang II, angiotensin II; As-Odns, antisense oligodeoxynucleotides; AT1R, angiotensin II receptor type 1; cAMP, cyclic adenosine monophosphate; CHO, Chinese hamster ovary; D1R, dopamine D1 receptor; D3R, dopamine D3 receptor; ETBR, endothelin receptor type B; GRK4, G protein-coupled receptor kinase 4; GSI, glomerular sclerosis index; hRPTCs: human renal proximal tubules cells; NHE: sodium-hydrogen exchanger; RPT, renal proximal tubule; SHRs, spontaneously hypertensive rats; siRNA, small interfering RNA; UTMD, ultrasound-targeted microbubble destruction; VSMCs, vascular smooth muscle cells; WKY, Wistar-Kyoto; WT, wild-type.