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Abstract: SA-PO776

Novel Evidence for an Enhanced Intrarenal Machinery of Estrogen Biosynthesis in the Female Rat Kidney

Session Information

  • Hypertension and CVD: Mechanisms
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

  • 1503 Hypertension and CVD: Mechanisms

Authors

  • Nasci, Victoria L., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Kriegel, Alison J., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Gohar, Eman Y., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Hypertension is more prevalent in men than age-matched pre-menopausal women. We recently showed that activation of the G-protein coupled estrogen receptor 1 in the renal medulla promotes natriuresis in female (F), but not male (M), Sprague Dawley (SD) rats. Whether renal medullary GPER1 is activated by circulating or locally produced estrogen is unknown. Some extragonadal tissues, such as the brain, express aromatase, the key enzyme in estrogen biosynthesis, which acts locally to convert testosterone to estradiol (E2). We hypothesized that the kidneys are capable of producing E2 and this intrarenal steroidogenic capability is enhanced in F rats.

Methods

To test this, we assessed the expression of elements of the estrogen biosynthesis pathway in M and F SD rat kidneys with a focus on the medulla as it plays a major role in sex-related differences in sodium handling.

Results

Mass spectrometry (MS) imaging of kidney sections revealed greater abundance for cholesterol sulfate, a substrate which can be used in sex steroid production, in F compared to M kidneys. This sex-specific difference in renal cholesterol abundance was driven by medullary differences (F: 4.98x106 ± 0.4 x106; M: 2.2 x106 ± 0.2 x106 average peak intensity P=0.0001). RNA sequencing of the renal inner medulla analyzed via Ingenuity Pathway Analysis revealed that 23% of sequenced transcripts encoding proteins within the estrogen biosynthesis pathway were greater, and 8% were lower, in F vs M rats, suggesting activation of this pathway in F kidneys. Of interest, Cyp19a1, which encodes for aromatase, was 2.7-fold higher in F compared to M inner medulla. Whereas inner medullary expression of Cyp2c11, which encodes an enzyme that converts testosterone to 2α-OH-testosterone, was 13-fold lower in F vs M. Increasing salt intake promoted Cyp19a1 mRNA expression in F, but not M, inner medulla (P=0.04). Using LC-MS, we found greater levels of tissue E2 within inner medullary tissues of F kidneys compared to M (28.9 ± 7.8 vs 9.3 ± 2.0 pg/µl/mg P=0.0323).

Conclusion

Overall, our investigation of renal estrogen biosynthesis reveals greater expression of the substrate, key enzyme, and end product as well as pathway enrichment in F compared to M kidneys. This points to the kidney as an extragonadal site for E2 biosynthesis, which could provide insight into sex-differences in renal disease.

Funding

  • NIDDK Support