T cell ROCK2 promotes DOCA-salt hypertension and end organ damage in a sex specific manner

Hypertension remains the leading modifiable risk factor for cardiovascular disease, yet many individuals continue to develop cardiac, vascular, or renal injury even after recommended blood pressure targets are reached. Prior work from our group has shown that Th17 activation and IL-17A contribute to the hypertensive phenotype and the associated tissue damage. Rho Associated Coiled-coil Containing Protein Kinase 2 (ROCK2) promotes Th17 differentiation and limits regulatory T cell (Treg) development, suggesting that ROCK2 activity in CD4 + T cells may influence immune responses during hypertension. Based on these observations, we hypothesized that ROCK2 in T cells contributes to hypertension and the associated end-organ injury in a sex-dependent manner, and that loss or inhibition of ROCK2 would alter these outcomes. We first confirmed that CD4 + T cells from deoxycorticosterone acetate (DOCA)-salt hypertensive mice exhibit increased ROCK2 expression. Using mice with T cell-specific deletion of Rock2, we observed reduced Th17 polarization in vitro and an attenuation of the hypertensive response in vivo. The blood pressure phenotype varied by sex. Female Rock2fl/flCD4Cre + mice showed an immediate and consistent reduction in blood pressure across the DOCA-salt protocol compared to Rock2fl/flCD4Cre- littermates (p=0.02 week 1, p=0.02 week 2, p=0.05 week 3, p=0.0008 effect of genotype across entire study), whereas males displayed a smaller change in pressure though still significantly lower (p=0.96 week 1, p=0.01 week 2, p=0.01 week 3, p< 0.0001 effect of genotype across entire study), but a marked reduction in structural injury. Male Rock2fl/flCD4Cre + mice exhibited lower cardiac hypertrophy (7.3±0.3 vs 6.1+/-0.3 mg/g heart weight/bodyweight, p< 0.01), reduced left ventricular fibrosis (9.1±1.6 vs 5.4+/0.5 % left ventricular area, p< 0.05), and decreased aortic fibrosis (20.5±1.8 vs 14.7±1.3 % aortic area, p< 0.05) compared to Rock2fl/flCD4Cre- littermates. In females, these remodeling outcomes were not significantly altered, consistent with the milder fibrotic response typically observed in female mice exposed to this model. Because patients usually present after hypertension is already established, we also examined the effects of a Rock2 selective inhibitor, KD025, in a delayed-treatment paradigm in male mice. KD025 did not change blood pressure, but CD4 + T cells from treated mice produced less IL-17A, and the balance of cardiac Treg to Th17 cells shifted toward a less inflammatory profile in the heart. Histological analysis demonstrated a halting in the progression of cardiac fibrosis and protection from aortic fibrosis with KD025 treatment. Furthermore, kidneys from KD025-treated mice had fewer T cells and less albuminuria. These results mirror the protection observed in the genetic Rock2fl/flCD4Cre + model. Overall, these findings show that ROCK2 in T cells contributes to both the hypertensive response and the associated tissue injury, and that these effects differ between males and females. The influence on blood pressure was more evident in females, whereas males lacking ROCK2 were better protected from cardiac and vascular remodeling. Although the basis for these differences is unclear, the data point toward a sex-specific role of ROCK2 in T cells during hypertensive stress. These results add to the evidence that adaptive immunity contributes to hypertension and highlight that the role of T cell ROCK2 may differ between sexes. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.