Rho kinase and PAI-1 in Bartter/Gitelman syndromes.: Relationship to angiotensin II signaling

Objective Angiotensin II (Ang II)-mediated activation of Rho kinase (ROK) is involved in the pathophysiology of hypertension and cardiovascular remodeling. ROK also controls plasminogen activator inhibitor-1 (PAI-1) which promotes vascular fibrosis contributing to atherogenesis. Bartter's and Gitelman's syndromes (BS/GS) are useful models to investigate abnormalities of vascular tone regulation, due to their reduced short- and long-term signaling pathways of Ang II. This study evaluated, using BS/GS as a model, ROK and PAI-1 gene and protein expression and the effect of Ang II co-incubation on ROK and PAI-1 gene and protein expression. Design, methods and results We measured ROK and PAI-1 gene and protein expression [reverse transcription-polymerase chain reaction (RT-PCR) and Western blot] in mononuclear cells (PBM) from one BS and eight GS patients. The effect of Ang II on ROK and PAI-1 gene and protein expression was also evaluated and compared with 10 controls. ROK gene and protein expression was reduced in BS/GS [0.47+/-0.11 densitometric units (d.u.) versus 0.70+/-0.04 d.u., P=0.0038 and 0.39+/-0.07 d.u. versus 0.55+/-0.07 d.u., P=0.0026, respectively]. The basal level of PAH gene and protein expression did not differ (0.40+/-0.03d.u. versus 0.39+/-0.02 d.u. and 0.81+/-0.02 d.u. versus 0.83+/-0.02 d.u., respectively). Ang II increased ROK and PAI-1 gene and protein expression only in controls: from 0.70+/-0.04 to 0.90+/-0.06 d.u., P=0.007 (ROK mRNA); from 0.55+/-0.07 to 0.86+/-0.07 d.u., P=0.0005 (ROK protein); from 0.40+/-0.02 to 0.63+/-0.03 d.u., P=0.001 (PAI-1 mRNA); and from 0.83+/-0.02 to 1.34+/-0.16 d.u., P=0.0023 (PAI-1 protein). Conclusions This study confirms BS/GS as a human model to investigate interrelated systems involved in the pathophysiology of hypertension and throws more light on the cellular mechanisms of BS/GS reduced Ang II short- and long-term signaling pathways.