Increased Expression of Regulator of G Protein Signaling-2 (RGS-2) in Bartter’s/Gitelman’s Syndrome. A Role in the Control of Vascular Tone and Implication for Hypertension

Abstract

Regulator of G protein signaling-2 (RGS-2) plays a key role in the G protein-coupled receptor (GPCR) angiotensin II (Ang II) signaling. NO and cGMP exert a vasodilating action also through activation and binding to RGS-2 of cGMP dependent protein kinase 1-alpha, which phosphorylates RGS-2 and dephosphorylates myosin light chain. In Bartter's/Gitelman's patients (BS/GS) Ang II related signaling and vasomotor tone are blunted. Experiments were planned to explore whether RGS-2 may play a role in BS/GS vascular hyporeactivity. NO metabolites and cGMP urinary excretion were also measured. Mononuclear cells (PBM) from six BS/GS patients and six healthy controls were used. PBM RGS-2 mRNA and RGS-2 protein were increased in BS/GS: 0.47 +/- 0.06 d.u. vs 0.32 +/- 0.04, (p < 0.006) (RGS-2 mRNA), and 0.692 +/- 0.02 vs 0.363 +/- 0.06 (p < 0.0001) (RGS2 protein). Incubation of PBM with Ang II increased RGS-2 protein in controls (from 0.363 +/- 0.06 d.u. to 0.602 +/- 0.05; p < 0.0001) but not in BS/GS (from 0.692 +/- 0.02 to 0.711 +/- 0.02). NO(2)(-)/NO(3)(-) and cGMP urinary excretion were increased in BS/GS (0.46 +/- 0.13 vs 0.26 +/- 0.05 micromol/micromol of urinary creatinine, p< 0.005, and 0.060 +/- 0.030 vs 0.020 +/- 0.01 p < 0.009, respectively). These results demonstrate that RGS-2 is increased and maximally stimulated in BS/GS and human RGS-2 system reacts as predicted by knockout mice experiments. This is the first report of RGS-2 level in a human clinical condition characterized by altered vascular tone, underlines the importance of RGS-2 as a key regulator element for Ang II signaling and provides insight into the links between BS/GS genetic abnormalities and abnormal vascular tone regulation.

Endothelial progenitor cells relationships with clinical and biochemical factors in a human model of blunted angiotensin II signaling

“…39 Furthermore, the increased number of EPC in BS/GS patients further strengthens the role of Ang II type 1 receptor signaling in EPC biology as BS/GS patients have blunted Ang II type 1 receptor signaling. [21][22][23][24][25][26][27][28] This linkage is further highlighted by the recent report of the beneficial effects of Ang II type 1 receptor blockers on EPCs number and function in hypertensive patients. 6,7 The extent to which the reported benefits may be derived from blocking Ang II type 1 receptors or signaling via Ang II type 2 receptors remains to be defined, although our recently published study, showing that in BS/GS, Ang II signaling via type 2 receptors is activated, 28 suggests that Ang II type 2 receptor signaling activation is potentially involved in the beneficial effects on EPCs.…”

“…For example, one could speculate that CD34+KDR+ cell phenotype may correlate with pathological vascular damage and increased CV risk, 48 while CD133+KDR+ and CD34+CD133+KDR+ are likely related to oxidative status and endothelial function as suggested by their status in BS/GS that is, increased CD133+KDR+ and CD34+CD133+KDR+ and unchanged CD34+KDR+, which fits with the biochemical, molecular and functional picture of good endothelial status reported in these patients. [16][17][18][19][20][21][22][23][26][27][28] In conclusion, the study documents in a human system that EPC numbers and specific populations are related to important clinical and biochemical factors involved in CV status. These results alongside the ongoing studies in our laboratory to quantitate calcitonin gene-related peptide and EPC status for example, senescence and proliferation in BS/GS, reaffirm the utility of BS/GS patients as a useful system to investigate EPC's role(s) in the pathophysiology of CV remodeling in humans.…”

“…15 The results of an extensive series of studies from our laboratory have provided mechanistic explanations for these patients' vascular hyporeactivity and absence of CV remodeling. [16][17][18][19][20] We have documented a blunted Ang II signaling and related pathways [21][22][23][24][25][26][27][28] in BS/GS patients. In addition, we have reported in BS/GS reduced oxidative stress alongside increased HO-1 gene expression, 29,30 upregulation of nitric oxide (NO) system 31,32 and increased NO-dependent vasodilation.…”

Identification of a cAMP-response Element in the Regulator of G-protein Signaling-2 (RGS2) Promoter as a Key Cis-regulatory Element for RGS2 Transcriptional Regulation by Angiotensin II in Cultured Vascular Smooth Muscles

“…Such polymorphisms would not alter the RGS2 * This work was supported, in whole or in part, by National Institutes of Health protein sequence but might affect RGS2 mRNA and protein expression levels, and reductions in RGS2 expression have been observed in cells from hypertensive patients with RGS2 gene polymorphisms (10,12). In contrast, increased RGS2 expression has been observed in cells from hypotensive patients with Bartter/Gitelman syndrome (13).…”

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

“…It has been reported that the RGS2 protein is overexpressed in patients with Bartter's syndrome (B/S) and Gitelman's syndromes (G/S), and that this abnormally high expression inhibits Ang II-mediated intracellular calcium release (Calo' et al, 1998) and promotes altered vascular remodeling. Indeed, fibroblasts taken from patients with B/S and G/S have enhanced RGS2 expression and reduced signaling through the AT1 receptor (Calo' et al, 2004), the effects of which can be normalized by the knockdown of RGS2 expression (Calo' et al, 2008).…”