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

• Published in: The journal of clinical endocrinology and metabolism 2004-08, Vol.89 (8), p.4153-4157
• Main Authors: Calò, Lorenzo A., Pagnin, Elisa, Davis, Paul A., Sartori, Michelangelo, Ceolotto, Giulio, Pessina, Achille C., Semplicini, Andrea
• Format: Article
• Language: English
• Subjects: Adult; Angiotensin II - pharmacology; Bartter Syndrome - metabolism; Case-Control Studies; Cohort Studies; Creatinine - urine; Cyclic GMP - urine; Female; Gene Expression; Humans; Hypertension - physiopathology; Middle Aged; Monocytes - metabolism; Nitrates - urine; Nitrites - urine; RGS Proteins - blood; RGS Proteins - genetics; RGS Proteins - metabolism; RNA, Messenger - metabolism; Vasomotor System - physiopathology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2004-0498

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-α, 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). NO2-/NO3- and cGMP urinary excretion were increased in BS/GS (0.46 ± 0.13 vs 0.26 ± 0.05 μmol/μmol 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.