Although myeloid‐cell RGS2 knockout does not affect Ang II –induced hypertension/organ damage in mice, high RGS2 in Gitelman/Bartter syndromes—human models of endogenous Ang II signaling antagonism—is associated with hypotensive/antiremodeling effects

Although myeloid-cell RGS2 knockout does not affect Ang II-induced hypertension/organ damage in mice, high RGS2 in Gitelman/Bartter syndromes-human models of endogenous Ang II signaling antagonism-is associated with hypotensive/antiremodeling effectsMyeloid cells are believed to contribute to hypertension by driving vascular inflammation, promoting T-cell activation, and regulating renal sodium retention (Hunter & Harrison, 2026).Yet Regulator of G-protein signaling 2 (RGS2) is highly expressed in myeloid cells, presenting a potential paradox given RGS2's negative regulatory activity on angiotensin (Ang) II signaling via Ang II type 1 receptors (AT1R) and their established role in hypertension and cardiovascular-renal remodeling (Heximer et al., 2003;Semplicini et al., 2006;Zhang et al., 2011).To probe this, Nakagawa and coworkers (Nakagawa et al., 2026) developed an elegant conditional myeloid-specific RGS2 knockout mouse model (RGS2 LysM-KO).Using this model, they documented the effects of chronic Ang II treatment, which, contrary to their own and general expectations, did not show any significant differences in blood pressure, cardiac and renal damage, vascular dysfunction, or inflammatory profiles in response to Ang II.These results led the authors to conclude that myeloid RGS2 is not involved in Ang II-induced hypertension or cardiovascular-renal organ damage (Nakagawa et al., 2026) and suggest that the severe, damaging hypertension seen in whole-body RGS2 deficiency is driven exclusively by altered RGS2 signaling in vascular and renal epithelial tissues, not the immune system.Given these results, we would like to offer some insights into RGS2 signaling that we have obtained using a human model of endogenous Ang II signaling antagonism, i.e., the mirror image of hypertension, Gitelman's and Bartter's syndromes (Calò et al., 2014).Gitelman's and Bartter's syndrome are rare genetic tubulopathies caused by gene defects in specific kidney transporters and