Abstract: FR-PO841
Healthy Women Have Higher Systemic Uromodulin Levels: Identification of Uromodulin as an Estrogen Responsive Gene
Session Information
- Women's Health and Kidney Diseases
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Women's Health and Kidney Diseases
- 2200 Women's Health and Kidney Diseases
Authors
- Nanamatsu, Azuma, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Micanovic, Radmila, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Khan, Shehnaz, Indiana University School of Medicine, Indianapolis, Indiana, United States
- El-Achkar, Tarek M., Indiana University School of Medicine, Indianapolis, Indiana, United States
- LaFavers, Kaice Arminda, Indiana University School of Medicine, Indianapolis, Indiana, United States
Background
Urinary and serum uromodulin (gene: UMOD), secreted by the kidney, gained attention as potential biomarkers for kidney function in the context of acute and chronic kidney diseases and as an overall marker of health. However, there are few analyses focusing on a large number of healthy subjects, and the ranges and physiological regulation of serum uromodulin have not been well established.
Methods
Using ELISA, we measured serum uromodulin levels of healthy human subjects (n = 380) available from the Indiana University Biobank. To identify predictors of levels, we performed automated linear modeling in SPSS using relevant predictor variables extracted from deidentified patient charts (age, sex, body mass index, race, serum creatinine, eGFR, prescription drug usage). We also measured serum uromodulin in mice using ELISA. To identify a potential mechanism for increased serum uromodulin levels in females, mouse kidney thick ascending limb (MKTAL) cells were treated with 17β-estradiol, and uromodulin mRNA and protein expression were evaluated by RT-qPCR and Western blotting, respectively.
Results
Healthy subjects showed a wide range of serum uromodulin levels. Automated linear modeling in SPSS identified sex and body mass index (BMI) as significant (p < 0.05) predictors of serum uromodulin level. Serum uromodulin levels are higher in healthy females than healthy males. To identify a potential mechanism for increased serum uromodulin levels in females, we analyzed the UMOD locus in H. sapiens and M. musculus. We found two non-canonical estrogen response elements (ERE) and 29 canonical half-EREs in the H. sapiens sequence and 45 canonical half-EREs in the M. musculus sequence. Consistent with this, serum uromodulin levels normalized to weight are higher in female mice. Additionally, treatment with 10 pM – 1 nM of 17β-estradiol increases uromodulin expression at the mRNA and protein levels in MKTAL cells.
Conclusion
Healthy females have higher serum uromodulin levels, likely due to the estrogen responsiveness of the UMOD gene. Since uromodulin has an immunomodulatory role and is protective against acute kidney injury, estrogen-responsive increases in serum uromodulin might partially explain sex-specific susceptibility to infection and kidney injury.
Funding
- NIDDK Support