Abstract Body: Menopause is associated with the loss of cardiovascular and renal protection, increasing the risk of hypertension and kidney disease. Although menopausal hormone therapy (MHT) offers multiple benefits, its effectiveness may depend on health status at the onset of menopause. Preexisting conditions such as hypertension may alter the response to estradiol and reduce the efficacy of MHT. Hypothesis: Hypertension established before menopause reduces the renal, cardiac, and vascular effects of estradiol. Methods: Female Long-Evans rats were ovariectomized at 46 weeks of age to simulate menopause and then randomly assigned to receive either estradiol (E2) or vehicle, serving as normotensive control groups. In a separate hypertensive group, rats were infused with angiotensin II (700 ng/kg/min) for 4 weeks prior to ovariectomy and continued for 4 additional weeks post-ovariectomy, during which they also received either E2 or vehicle. Blood pressure (BP), renal function (proteinuria and estimated glomerular filtration rate-eGFR), renal collagen deposition, and GPER, ERα, and NOX4 expression were measured using droplet digital PCR. Data were analyzed by two-way ANOVA. Results: Angiotensin II significantly increased BP (p<0.05), water intake and urinary output (p<0.01), proteinuria (p<0.01), heart weight (p<0.01), and NOX4 expression in the aorta (p<0.01), confirming the induction of hypertension and vascular oxidative stress. E2 reduced body weight (p<0.05) and prevented uterine atrophy (p<0.01), confirming systemic estrogenic effects. While E2 attenuated cardiac hypertrophy (p<0.01), it did not affect kidney hypertrophy. Importantly, E2 failed to improve vascular oxidative stress, as it did not reduce NOX4 expression in the aorta. In the renal cortex, E2 downregulated ERα (p<0.05) and upregulated GPER (p<0.01), but had no effect on receptor expression in the aorta. Despite a trend toward reduced collagen deposition in the renal cortex (p=0.08), E2 worsened renal function by increasing proteinuria (p<0.05) and decreasing eGFR (p<0.01), independently of BP. Conclusion: These findings suggest that in an aging hypertensive model of menopause, E2 did not provide protection against renal and vascular damage. This highlights the importance of considering health status at menopause when considering MHT.