DOCA-salt-induced hypertension significantly increased blood pressure in female compared to male mice (141 vs 114 mmHg; P<0.01) and decreased renal Xist expression (P=0.0402).
Does DOCA-salt-induced hypertension downregulate Xist expression and promote kidney damage in female mice?
DOCA-salt-induced hypertension decreases Xist expression in the kidney of female mice, which is associated with increased arterial stiffness and renal damage.
Absolute Event Rate: 141% vs 114%
p-value: p=<0.01
Background: X-chromosome inactivation (XCI) ensures equal expression of X-linked genes in males (XY) and females (XX). Xist plays a crucial role in the XCI process by coating the inactive X in cis during embryonic development. Studies have shown Xist's involvement in lupus, a disease predominantly affecting females with significant kidney damage. However, the role of Xist in hypertension remains unknown. Hypothesis: We hypothesized that the downregulation of Xist in the kidneys of hypertensive female mice promotes kidney damage. Methods: We used the DOCA (50mg) -salt (1%) -induced hypertension model in age-matched gonadectomized female and male mice for 21 days. Blood pressure was measured by radiotelemetry, aortic pulse wave velocity by Pulse Wave Doppler, and mesenteric vascular reactivity by myography. Flow cytometry and RT-PCR were used for immune cells and gene expression. Masson trichrome staining was used to assess kidney fibrosis. The data was analyzed using unpaired sample t-test for non-parametric studies between male and female mice and a paired sample t-test before and after DOCA-salt treatment on the female mice. At baseline, mean arterial blood pressure was greater but not significantly different in female than male mice (109 mmHg vs. 105 mmHg). However, PWV was greater in female than in male mice (3. 8 m/s vs. 2. 9 m/s; P< 0. 05). DOCA-induced hypertension significantly increased blood pressure in female mice compared with male mice (141 mmHg vs. 114 mmHg; P< 0. 01). However, no significant differences were detected in arterial stiffness (5. 2 m/s vs. 4. 9 m/s). Since males do not express Xist, we afterward compared female mice with and without DOCA-salt treatment. Female mice with DOCA-salt-induced hypertension showed no significant differences in Phenylephrine-mediated constriction; however, there was a significant decrease in Acetylcholine (Ach) -mediated relaxation (Ach 10^-5: 55% vs. 28%) and Sodium Nitroprusside-mediated relaxation (SNP 10^-7: 78% vs. 48%). DOCA-treated mice had a 2-fold increase in water intake and urinary volume, and increased proteinuria. Renal T cell assessment showed increased CD3 (P< 0. 05) and CD8 (P= 0. 0184) positive cells. Histological analysis revealed increased aortic and renal fibrosis in DOCA-treated female mice. Gene expression analysis in kidney samples revealed decreased levels of Xist (P = 0. 0402), Agtr1a (P< 0. 05), and renin (P< 0. 001). Our data suggest that DOCA-induced hypertension decreases Xist expression in the kidney, thereby promoting arterial stiffness and renal damage. Therefore, inhibiting Xist-targeted genes can reduce DOCA-induced vascular damage in female mice. Sources of Funding This work was supported by the NIH grants: NIH R00HL155841 & U54HLL169191 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.
Aboagye et al. (Fri,) conducted a other in Hypertension. DOCA-salt vs. Male mice and untreated female mice was evaluated on Mean arterial blood pressure (p=<0.01). DOCA-salt-induced hypertension significantly increased blood pressure in female compared to male mice (141 vs 114 mmHg; P<0.01) and decreased renal Xist expression (P=0.0402).