Philipp Lachenmann: DELPHI Rationale


Schoeller Junkmann Preis 2005

Dr. Markus Quinkler

Klinische Endrokrinologie, Charité - Universitätsmedizin Berlin

Testosterone directly enhances mRNA expression of the alpha-subunit of the epithelial sodium channel (aENaC) in a human kidney derived cell line HKC-8

Background: Rodents studies suggest that androgens are involved in sex-specific differences in blood pressure. In humans there is no difference in blood pressure between boys and girls, but following puberty, blood pressure increases more in men than in women. Modulation of epithelial sodium reabsorption through the expression and activity of ENaC is an important component controlling sodium balance and blood pressure.

Methods: We investigated the androgen-dependent regulation of aENaC in human kidney and a human renal cell line HKC-8. Androgen receptor (AR) expression was studied on mRNA and protein levels. We used Affymetrix microarray techniques to analyse androgen-dependent gene regulation in HKC-8 cells and performed Taq Man quantitative RT-PCR for verification. HKC-8 cells were transfected with different human aENaC promoter-reporter constructs and regulation by testosterone studied.

Results: The AR was expressed in male kidney and HKC-8 cells. aENaC mRNA expression increased 2-3-fold following treatment with testosterone in HKC-8 cells as measured by microarray and quantitative RT-PCR. The induction by testosterone was completely blocked by adding the AR antagonist flutamide. Transcription factor database analysis (using TESS) of the aENaC promoter sequence identified a putative AR response element (ARE) located 140 nucleotides upstream from the transcription start-site of exon 1A. HKC-8 cell transfection studies showed that testosterone directly up-regulated gene expression via this ARE.

Conclusions: These data show that aENaC expression is regulated directly by androgens and highlight a potential mechanism explaining the reported gender differences in blood pressure.



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