Effect of 17β-estradiol on the daily pattern of ACE2, ADAM17, TMPRSS2 and estradiol receptor transcription in the lungs and colon of male rats

PLoS One. 2022 Jun 28;17(6):e0270609. doi: 10.1371/journal.pone.0270609. eCollection 2022.

Abstract

Covid-19 progression shows sex-dependent features. It is hypothesized that a better Covid-19 survival rate in females can be attributed to the presence of higher 17β-estradiol (E2) levels in women than in men. Virus SARS-CoV-2 is enabled to enter the cell with the use of angiotensin converting enzyme 2 (ACE2). The expression of several renin-angiotensin system components has been shown to exert a rhythmic pattern, and a role of the circadian system in their regulation has been implicated. Therefore, the aim of the study is to elucidate possible interference between E2 signalling and the circadian system in the regulation of the expression of ACE2 mRNA and functionally related molecules. E2 was administered at a dosage of 40 μg/kg/day for 7 days to male Wistar rats, and sampling of the lungs and colon was performed during a 24-h cycle. The daily pattern of expression of molecules facilitating SARS-CoV-2 entry into the cell, clock genes and E2 receptors was analysed. As a consequence of E2 administration, a rhythm in ACE2 and TMPRSS2 mRNA expression was observed in the lungs but not in the colon. ADAM17 mRNA expression showed a pronounced rhythmic pattern in both tissues that was not influenced by E2 treatment. ESR1 mRNA expression exerted a rhythmic pattern, which was diminished by E2 treatment. The influence of E2 administration on ESR2 and GPER1 mRNA expression was greater in the lungs than in the colon as a significant rhythm in ESR2 and GPER1 mRNA expression appeared only in the lungs after E2 treatment. E2 administration also increased the amplitude of bmal1 expression in the lungs, which implicates altered functioning of peripheral oscillators in response to E2 treatment. The daily pattern of components of the SARS-CoV-2 entrance pathway and their responsiveness to E2 should be considered in the timing of pharmacological therapy for Covid-19.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM17 Protein* / genetics
  • Angiotensin-Converting Enzyme 2* / genetics
  • Animals
  • COVID-19 Drug Treatment*
  • COVID-19* / virology
  • Colon* / drug effects
  • Colon* / metabolism
  • Estradiol* / pharmacology
  • Female
  • Lung* / metabolism
  • Male
  • Peptidyl-Dipeptidase A / metabolism
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Rats
  • Rats, Wistar
  • Receptors, Estradiol* / genetics
  • Receptors, Estradiol* / metabolism
  • SARS-CoV-2 / physiology
  • Serine Endopeptidases / genetics
  • Transcription, Genetic / drug effects
  • Virus Internalization

Substances

  • RNA, Messenger
  • Receptors, Estradiol
  • Estradiol
  • Peptidyl-Dipeptidase A
  • Ace2 protein, rat
  • Angiotensin-Converting Enzyme 2
  • Serine Endopeptidases
  • Tmprss2 protein, rat
  • ADAM17 Protein
  • Adam17 protein, rat

Grants and funding

This work was supported by APVV-16-0209, The Slovak Research and Development Agency, https://www.apvv.sk/?lang=en, to IH; APVV-20-0241, The Slovak Research and Development Agency, https://www.apvv.sk/?lang=en, to IH; VEGA 1/0679/19, Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic, https://www.minedu.sk/vedecka-grantova-agentura-msvvas-sra-sav-vega/, to IH; Operation Program of Integrated Infrastructure for the project, Advancing University Capacity and Competence in Research, Development and Innovation, ITMS2014+: 313021X329, co-financed by the European Regional Development Fund to LO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.