Background: Both menopause and hypertension independently accelerate renal injury, and their coexistence creates a particularly high-risk condition for postmenopausal women. Emerging evidence suggests that, under pathological states, estrogen may exert paradoxical effects—failing to protect the kidney and potentially worsening damage. Whether estradiol (E2) therapy is beneficial or detrimental appears to depend on the underlying health status, yet the mechanisms driving these context-dependent responses remain poorly understood. This study examined how E2 influences renal injury in normotensive and Ang II-induced hypertensive models of menopause. Methods: Female Long-Evans rats were ovariectomized (OVX) at 46 weeks of age to model menopause and randomized to receive vehicle (VEH) or estradiol (E2) via silastic capsule. Rats were further assigned to remain normotensive (NT) or receive chronic angiotensin II infusion (Ang II; 700 ng/kg/min) to induce hypertension (ANG). Renal outcomes included proteinuria, tubular casts, cortical and medullary collagen content, and estrogen receptor expression, and statistical analysis was performed with two-way ANOVA. Results: E2 significantly increased water intake, urine output, and proteinuria in both NT and ANG rats (p < 0.05). Tubular injury was strongly modified by hypertensive status: E2 caused only a modest rise in tubular casts in NT rats but markedly exacerbated cast formation in ANG rats. In the cortex, ANG robustly increased glomerular and tubular collagen deposition (p < 0.001), and E2 did not attenuate this response. E2 also altered cortical estrogen receptor expression, reducing ERα (p = 0.009) and increasing GPER (p = 0.03). In the medulla, collagen showed a trend toward an ANG × E2 interaction (p = 0.07), while E2 selectively reduced ERα expression (p = 0.002) without affecting GPER. Conclusion: E2 worsened proteinuria, impaired fluid handling, and substantially increased tubular cast formation—effects that were most pronounced in hypertensive rats. Combined with shifts in estrogen receptor signaling and lack of antifibrotic protection, these findings demonstrate that E2 exacerbates renal dysfunction in this hypertensive rat model of menopause. These findings underscore the importance of underlying cardiovascular health when considering menopausal hormone therapy. Further studies are needed to clarify the mechanisms by which E2 promotes renal damage and to identify conditions under which hormone therapy may be safely applied. This work was funded by NHI AG071746 and AHA Postdoctoral Fellowship 25POST1375284. 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.
Leite et al. (Fri,) studied this question.