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.
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.
Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Italy. renzcalo@unipd.it
Lorenzo A
LA
Calò
Elisa
E
Pagnin
Paul A
PA
Davis
Michelangelo
M
Sartori
Giulio
G
Ceolotto
Achille C
AC
Pessina
Andrea
A
Semplicini
D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology; D001477:Bartter Syndrome / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D003404:Creatinine / Q000652:urine; D006152:Cyclic GMP / Q000652:urine; D005260:Female; D015870:Gene Expression; D006801:Humans; D006973:Hypertension / Q000503:physiopathology; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009566:Nitrates / Q000652:urine; D009573:Nitrites / Q000652:urine; D020710:RGS Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014666:Vasomotor System / Q000503:physiopathology*
D009566:Nitrates; D009573:Nitrites; D020710:RGS Proteins; C087182:RGS2 protein, human; D012333:RNA, Messenger; D000804:Angiotensin II; D003404:Creatinine; D006152:Cyclic GMP