Abstract: FR-PO405
Evidence of Estrogen Biosynthesis in the Rat Distal Nephron
Session Information
- Hypertension and CVD: Basic
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1601 Hypertension and CVD: Basic
Authors
- Nasci, Victoria L., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Sugahara, Sho, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Brooks, Craig R., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Gohar, Eman Y., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
Estrogenic signaling via renal medullary G protein-coupled estrogen receptor 1 promotes sodium excretion in female, but not male, Sprague Dawley (SD) rats implicating estrogen as a potential female-specific natriuretic factor. Recently we showed that the components of estrogen biosynthesis pathway are expressed in rat kidney suggesting the kidneys can produce estrogen locally to invoke this natriuretic response. However, the renal localization and biological activity of aromatase (ARO), the key enzyme in estrogen synthesis, are still not fully clear. The goal of this study was to determine ARO abundance, localization, binding, and levels of ARO end products in male and female SD rat kidneys.
Methods
We utilized immunohistochemistry (IHC) and immunofluorescence (IF) to determine abundance and localization, a radiotracer to evaluate in vivo binding to ARO, and mass spectrometry to measure estrogens.
Results
IHC analysis revealed ARO was most abundant in cortex (CTX) and outer medulla (OM) with a less intense signaling in the inner medulla (IM) in both sexes (male: CTX 2.4 ± 0.31, OM 1.8 ± 0.19, IM 0.6 ± 0.15 p=0.0002; female: CTX 2.6 ± 0.27 OM 2.0 ± 0.21 IM 1.2 ± 0.31 p=0.0074 Average intensity x total area mM2). IHC analysis of male and female kidney showed the expression of ARO primarily in the distal nephron with little staining in the proximal tubule and glomeruli. IF staining for ARO and aquaporin 2 showed colocalization indicating that ARO is expressed in the collecting duct. Preliminary positron emission tomography scan of female rats following tail vein injection of [11C]-cetrozole, a radiolabeled ARO inhibitor, revealed binding, indicating ARO-rich regions, within the kidneys, but not the lungs or muscle (2.9 ± 0.16 vs 0.9 ± 0.31 & 0.4 ± 0.04 respectively p=0.0063 Standard uptake value). Estradiol and estrone were present in both male and female OM isolated from flushed kidneys (estradiol; 0.9 ± 0.15 vs 1.0 ± 0.21 p=0.7627, estrone; 0.2 ± 0.05 vs 0.3 ± 0.01 pg/mg tissue p=0.0630).
Conclusion
Overall, our investigation indicates the potential of the rat collecting duct as an extragonadal site for estrogen biosynthesis. Given the critical role of the collecting duct in fine tuning of sodium excretion, improving our understanding of the contribution of kidney-derived estrogens to renal sodium handling and hypertension could reveal novel antihypertensive therapeutic avenues.
Funding
- NIDDK Support