Renal Actions of RGS2 Control Blood Pressure

Abstract

The role of G protein-coupled receptors (GPCRs) in hypertension and cardiovascular diseases is well established. 1 Moreover, pharmacologic antagonists of GPCRs, such as ␤-adrenergic and angiotensin receptors, are cornerstones of therapy in the treatment of hypertension and its complications. 2 Signaling by GPCRs is triggered by ligand-induced conformational changes in the receptor that promote exchange of guanosine 5Ј-diphosphate for guanosine 5Ј-triphosphate on the G␣ subunit of the G protein complex, 3 followed by dissociation of G␣ from the G␤␥ dimer. The dissociated subunits can then interact with effector molecules to propagate the signal. The duration and intensity of signaling are further regulated by GTPase-activating proteins. 4 The regulators of G protein signaling (RGSs) are a family of proteins with GTPase-activating protein activity. 4 Among these, RGS2 displays regulatory selectivity for the G␣q subclass of G proteins. 5 Many key cardiovascular hormones such as angiotensin II, endothelin-1, thromboxane A 2 , and norepinephrine activate receptors that couple to G␣q.A specific role for RGS2 in maintaining normal vascular tone and BP was established using genetically modified mice. 6,7 RGS2-deficient mice have hypertension 6,7 along with abnormal vascular contraction and relaxation responses. 7 In addition to its actions to influence the contractile state of vascular smooth muscle, regulated expression of RGS2 has been described in other tissues that are important for BP regulation including the central nervous system 8 and the kidney. 9 Here, we use a kidney crosstransplantation strategy to distinguish contributions of RGS2 actions in the kidney from extrarenal tissues to the regulation of BP and the development of hypertension. Our studies indicate that RGS2 effects within the kidney are critical for regulation of BP, suggesting that altered renal epithelial and/or vascular functions are responsible for hypertension in this genetic model.To determine the relative contributions of RGS2 in renal versus extrarenal tissues to the pathogenesis of hypertension, we used a kidney crosstransplantation strategy. By varying the genotype of the transplant donor and recipient, we generated four groups of animals in which renal function was provided entirely by the single transplanted kidney. The wild-type group consisted of wildtype mice transplanted with kidneys from wild-type donors, having normal expression of RGS2 in the kidney transplant and in all systemic tissues. For the systemic knockout (KO) group, RGS2-deficient recipients were transplanted with kidneys from wild-type donors; these animals lack RGS2 in all tissues except the kidney. Kidney KO animals are wild-type recipients of RGS2-deficient kidneys lacking expression of RGS2 only in renal parenchyma and vasculature but with normal expression of receptors in ABSTRACTG protein-coupled receptors (GPCRs) have key roles in cardiovascular regulation and are important targets for the treatment of hypertension. GTPase-activating proteins, such as RGS2, mod...

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

“…RGS2 protein levels were also increased in the kidney (Fig. 6B), where RGS2 has been proposed to exert effects on blood pressure homeostasis (Gurley et al, 2010).…”

Regulators of G-Protein Signaling and Their Gα Substrates: Promises and Challenges in Their Use as Drug Discovery Targets

“…These studies have identified single nucleotide polymorphisms within the coding region of RGS2 that result in a decrease of proper localization of RGS2 to the plasma membrane and a resultant decrease of its inhibitory influence on G␣ qmediated vasoconstrictive hormone signal transduction (Yang et al, 2005;Gu et al, 2008). Promoter polymorphisms in the RGS2 gene locus and renal actions of RGS2 have also been highlighted as contributing factors to the intrinsic homeostatic and extrinsic therapeutic control of blood pressure maintenance (Gurley et al, 2010;Semplicini et al, 2010;Sugimoto et al, 2010). In addition, the RGS2-deficient mouse was instrumental in demonstrating the role for RGS2 protein action in cardiac compensation to blood pressure overload and the antihypertrophic effects of PDE5 inhibition (Takimoto et al, 2009).…”

RGS2 Proteins Regulate Blood Pressure

“…Mice lacking RGS2 develop hypertension for unknown reasons. 8 Gurley et al 7 now show that transplanting kidneys from hypertensive RGS2 Ϫ/Ϫ mice increases BP in wildtype mice, demonstrating the dominant effect of the kidneys for this gene.…”

“…In this issue of JASN, Gurley et al 7 use the cross-transplantation method to study the role of the regulator of G protein signaling type 2 (RGS2) that is implicated in hypertension. There is growing evidence that G proteincoupled receptor (GPCR)-mediated control of vascular tone and BP is an important regulatory step in the development of hypertension.…”

“…3,4 The most likely story of tubular uptake has been unveiled in a series of beautiful experiments, some of which are based on genetic disorders in humans and mice. 3,[5][6][7][8][9][10][11] After endocytosis, the megalin-cubilin complex delivers its ligands to lysosomes, where all proteins are degraded and the amino acids and vitamins are returned to the circulation. 12 These studies have been highly relevant clinically for several reasons: First, they shed light on the nephrotoxicity and ototoxicity of aminoglycosides.…”