Kidney Week

Abstract: FR-PO0980

Endothelin Receptor A Antagonism Attenuates Hypertension in Aged Female GPER1 Knockout Mice

Session Information

• Women's Health and Kidney Diseases
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Women's Health and Kidney Diseases

• 2100 Women's Health and Kidney Diseases

Authors

• Singh, Ravneet, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ravneet Singh

• Ross, Ian Tweed, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ian Tweed Ross

• Buehler, Dennis P., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Dennis P. Buehler

• Gohar, Eman Y., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Eman Y. Gohar, MS, PhD

Background

Hypertension prevalence increases with age in women coinciding with declining ovarian estrogen production. Estrogen contributes to blood pressure (BP) regulation in female rodents, in part through G-protein-coupled estrogen receptor 1 (GPER1). Aged female mice lacking GPER1 have high BP. GPER1 variants are associated with increased systolic BP in nulliparous women older than 55 years. GPER1 regulates the endothelin-1 (ET-1) system, which signals through endothelin receptor subtype A (ET_A) and B (ET_B). We hypothesized that GPER1 deletion promotes ET_A-mediated hypertension.

Methods

14–18-month-old GPER1 wild-type (WT) and global knock-out (KO) female mice were placed in metabolic cages to collect 24-hour urine samples (n=6-7/group) for ET-1 assessment. Kidneys were harvested for assessment ET_A and ET_B mRNA expression (n=4-6/group). Aortic ET_A and ET_B mRNA expression were assessed in 20-22 month-old GPER1 WT and KO female mice (n=4-7/group).Given the established vasoconstrictive role of ET_A, atrasentan (an ET_A antagonist) was used to determine the contribution of ET_A to hypertension in GPER1 KO mice. Specifically, radiotelemetry transmitters were implanted in 20-22-month-old GPER1 KO female mice and BP and heart rate were recorded during treatment with vehicle, then treatment with atrasentan (10 mg/Kg/day for 3 weeks, n=9/group).

Results

GPER1 deletion increased urinary ET-1 excretion (0.37±0.06 vs. 0.17±0.01 pg/day, p=0.0043). No differences were observed in response to GPER1 deletion in renal cortical ET_A and ET_B expression. Compared to age-matched WT mice, GPER1 KO mice elicited greater aortic expression of ET_A (1.00±0.19 vs. 2.03± 0.34 fold change, respectively; p=0.0195), but not ET_B. A three-week atrasentan treatment reduced mean arterial pressure in GPER1 KO compared to corresponding vehicle-treated values (114±2 vs.122±2 mmHg, respectively; p<0.0001). Similarly, it decreased systolic BP (129±2 vs.139±2 mmHg, respectively; p<0.0001), and diastolic BP compared to corresponding vehicle values (98±2 vs.105±2 mmHg, respectively; p=0.0001). Heart rate remained unchanged (604±16 vs. 602±7 beats/minute respectively; p>0.9999).

Conclusion

Our data suggest that ET_A contributes to the increase in BP evident in aged female mice lacking GPER1, possibly via increased vasoconstriction. These findings may provide insight regarding potential therapeutic targets for postmenopausal hypertension.

Funding

• Other NIH Support