Figure 3.

Schematic representation of Angiotensin II-mediated pathways involving RhoA/ROCK in arterial hypertension (A) and Bartter’s and Gitelman’s syndromes (B). Angiotensin II, via angiotensin II type 1 receptor (AT1R), activates the cascade RhoGEF/RhoA/ROCK, which leads to vascular remodeling, cardiac and renal fibrosis, and atherogenesis in hypertension (Panel A). The sketch reports the NF-κB/PAI-1 and NADPH oxidase/ superoxide anion (O₂⁻) as representative ROCK downstream pathways, but other pathways can be involved (see Figure 2). AT1-mediated pathways also involve mitogen-activated protein kinases (MAPK and ERK 1/2), diacylglycerol (DAG)/protein kinase C (PKC) and inositol triphosphate (IP3), which leads to increased Ca²⁺ release in the cytosol with vasoconstriction. In Bartter’s and Gitelman’s syndromes (Panel B), despite increased levels of Angiotensin II, the pathways leading to vasodilatation prevail on those leading to vasoconstriction due to post receptor abnormalities including blunted Gαq protein signaling and activation of the regulatory G protein signaling 2 (RGS2). RGS2 causes activation of endothelial nitric oxide synthase (eNOS) with increased Nitric Oxide (NO) release and blunted ROCK activity and signaling, with reduced intracellular Ca²⁺ sensitivity finally leading to vasodilation. Modified from Calò, L.A. et al. [1,25].