Increased Renal Responsiveness to Vasopressin and Enhanced V2 Receptor Signaling in RGS2 −/− Mice

Zuber, Annie Mercier; Singer, Dustin; Penninger, Josef; Rossier, Bernard C.; Firsov, Dmitri

doi:10.1681/asn.2007010032

Cited by 33 publications

(23 citation statements)

References 20 publications

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“…Moreover, through the ability of its N-terminal domain to directly inhibit specific adenylate cyclase isoforms (Gu et al, 2008b;Salim et al, 2003), RGS2 may attenuate signaling via receptors for dopamine and vasopressin in the kidney. Consistent with this suggestion, RGS2 was shown to regulate vasopressin responses in cortical collecting duct segments in vivo (Zuber et al, 2007).…”

Section: Rgs2 Inhibits Gαq and Adenylatecyclase-mediated Signalingsupporting

confidence: 67%

Resistant Hypertension, Elevated Aldosterone/Renin Ratio and Reduced RGS2: A Pathogenetic Link Deserving Further Investigations?

Semplicini¹,

Stella²,

Ceolotto³

2012

Genetics and Pathophysiology of Essential Hypertension

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Section: Rgs2 Inhibits Gαq and Adenylatecyclase-mediated Signalingsupporting

confidence: 67%

Resistant Hypertension, Elevated Aldosterone/Renin Ratio and Reduced RGS2: A Pathogenetic Link Deserving Further Investigations?

Semplicini¹,

Stella²,

Ceolotto³

2012

Genetics and Pathophysiology of Essential Hypertension

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“…RGS2 proteins are expressed in a variety of tissues including smooth muscle, heart, bone, immune system, olfactory epithelium, and brain [see review (5)]. RGS2 deletion in mice resulted in cardiovascular phenotypes including hypertension, cardiac hypertrophy, and developed renovascular abnormalities with increased responsiveness to vasopressin (5,25,101). RGS2 might play a role in the development of genetic cardiovascular diseases since RGS2 expression was enhanced in Bartter's/Gitelman's syndrome patients suffering from hypotension, diminished angiotensin-II signaling, and vasomotor tone (9).…”

Section: Other Targets For Pkgmentioning

confidence: 99%

IRAG and novel PKG targeting in the cardiovascular system

Schlossmann

Desch

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Schlossmann J, Desch M. IRAG and novel PKG targeting in the cardiovascular system. Am J Physiol Heart Circ Physiol 301: H672-H682, 2011. First published June 10, 2011; doi:10.1152/ajpheart.00198.2011.-Signaling by nitric oxide (NO) determines several cardiovascular functions including blood pressure regulation, cardiac and smooth muscle hypertrophy, and platelet function. NO stimulates the synthesis of cGMP by soluble guanylyl cyclases and thereby activates cGMP-dependent protein kinases (PKGs), mediating most of the cGMP functions. Hence, an elucidation of the PKG signaling cascade is essential for the understanding of the (patho)physiological aspects of NO. Several PKG signaling pathways were identified, meanwhile regulating the intracellular calcium concentration, mediating calcium desensitization or cytoskeletal rearrangement. During the last decade it emerged that the inositol trisphosphate receptor-associated cGMP-kinase substrate (IRAG), an endoplasmic reticulum-anchored 125-kDa membrane protein, is a main signal transducer of PKG activity in the cardiovascular system. IRAG interacts specifically in a trimeric complex with the PKG1␤ isoform and the inositol 1,4,5-trisphosphate receptor I and, upon phosphorylation, reduces the intracellular calcium release from the intracellular stores. IRAG motifs for phosphorylation and for targeting to PKG1␤ and 1,4,5-trisphosphate receptor I were identified by several approaches. The (patho)physiological functions for the regulation of smooth muscle contractility and the inhibition of platelet activation were perceived. In this review, the IRAG recognition, targeting, and function are summarized compared with PKG and several PKG substrates in the cardiovascular system. inositol trisphosphate receptor-associated guanosine 3=,5=-cyclic monophosphatekinase substrate; nitric oxide; guanosine 3=,5=-cyclic monophosphate-dependent protein kinase THIS ARTICLE is part of a collection on Hypertension and Novel Modulators of Vascular Tone. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.Nitric oxide (NO) leads to cGMP synthesis and thereby activates cGMP-dependent protein kinase (PKG), mediating various cardiovascular functions. The identification of PKG substrates including the inositol trisphosphate receptor-associated cGMP-kinase substrate (IRAG) has lead to a new view of PKG1 isozyme PKG1␤ and PKG1␣ function. Intracellular targeting and function of these isozymes are modulated by different substrates. The recognition of these substrates is mediated by the NH 2 -terminal leucine/isoleucine zipper (LZ) domains of PKG1. In this review the current view of the molecular interaction and function of IRAG compared with other substrates regulated by PKG are described, mainly focusing on the cardiovascular system. Furthermore, the subtle pathways for cGMP/PKG signaling are discussed. Function of NO/cGMP/PKG Signaling CascadeNO/cGMP signaling regulates several tasks in the cardiovascular sy...

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“…In addition, GPCRs expressed along the renal vasculature regulate renal blood flow and thereby have secondary effects to influence renal sodium handling. 24 For example, renal vasoconstriction caused by angiotensin II reduces medullary blood flow, thus blunting the kidney's excretory capacity for sodium. 25 RGS2 would attenuate these actions, and these effects may be exaggerated in RGS2-deficient mice, potentially promoting hypertension.…”

mentioning

confidence: 99%

Renal Actions of RGS2 Control Blood Pressure

Gurley¹,

Griffiths²,

Mendelsohn³

et al. 2010

Journal of the American Society of Nephrology

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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...

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Increased Renal Responsiveness to Vasopressin and Enhanced V2 Receptor Signaling in RGS2 −/− Mice

Cited by 33 publications

References 20 publications

Resistant Hypertension, Elevated Aldosterone/Renin Ratio and Reduced RGS2: A Pathogenetic Link Deserving Further Investigations?

Resistant Hypertension, Elevated Aldosterone/Renin Ratio and Reduced RGS2: A Pathogenetic Link Deserving Further Investigations?

IRAG and novel PKG targeting in the cardiovascular system

Renal Actions of RGS2 Control Blood Pressure

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