Download PDF
Horm Metab Res 2009; 41(5): 356-362
DOI: 10.1055/s-0029-1192033
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Sex-specific Regulation of ENaC and Androgen Receptor in Female Rat Kidney

T. Kienitz 1 , B. Allolio 2 , C. J. Strasburger 1 , M. Quinkler 1
  • 1Clinical Endocrinology, Department of Internal Medicine, Gastroenterology, Hepatology and Endocrinology, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany
  • 2Department of Endocrinology, Medical University Würzburg, Würzburg, Germany
Further Information

Publication History

received 05.10.2008

accepted 07.01.2009

Publication Date:
17 February 2009 (online)

Also available at
    Permissions and Reprints

Abstract

With the beginning of puberty blood pressure increases and is persistently higher in men than in premenopausal women. Sex steroids are known to have complex effects on the renal and cardiovascular system and are involved in blood pressure regulation. The epithelial sodium channel (ENaC) modulates sodium reabsorption in the kidney, but little is known about sex-specific regulation of ENaC subunit expression. Regulation of the androgen receptor (AR) is known to be tissue-specific and age-dependent, but not well studied in the kidney. We investigated the effects of sex steroids on ENaC subunits and renal AR expression in an in vivo rat model. Ovariectomized female Wistar rats were treated with placebo, testosterone, 5 α-dihydrotestosterone (DHT) or 17 β-estradiol (E2) for 14 days, and quantitative PCR and Western immunoblots were performed. DHT significantly decreased expression of all ENaC subunits in female rats, whereas testosterone showed only a trend to lower ENaC expression. These results are in contrast to previous studies where stimulating effects of androgens on the alpha-subunit of ENaC were seen. AR mRNA expression showed a trend to lower levels in females after testosterone treatment in this study. However, estrogen treatment significantly downregulated AR mRNA expression. In male control animals we were able to show a significantly increased expression of AR mRNA upon testosterone treatment. Our data demonstrate that AR and ENaC are regulated by sex steroids. That way sex steroids might modulate renal sodium reabsorption and therefore provide a possible explanation for sex differences in blood pressure.

Key words

androgens - androgen receptor - blood pressure - epithelial sodium channel - sex steroids - testosterone

References

  • 1 Harshfield GA, Alpert BS, Pulliam DA, Somes GW, Wilson DK. Ambulatory blood pressure recordings in children and adolescents.  Pediatrics. 1994;  94 180-184
    Google Scholar
  • 2 Himmelmann A, Svensson A, Hansson L. Influence of sex on blood pressure and left ventricular mass in adolescents: the Hypertension in Pregnancy Offspring Study.  J Hum Hypertens. 1994;  8 485-490
    Google Scholar
  • 3 Wiinberg N, Hoegholm A, Christensen HR, Bang LE, Mikkelsen KL, Nielsen PE, Svendsen TL, Kampmann JP, Madsen NH, Bentzon MW. 24-h ambulatory blood pressure in 352 normal Danish subjects, related to age and gender.  Am J Hypertens. 1995;  8 978-986
    Google Scholar
  • 4 Yong LC, Kuller LH, Rutan G, Bunker C. Longitudinal study of blood pressure: changes and determinants from adolescence to middle age. The Dormont High School follow-up study, 1957–1963 to 1989–1990.  Am J Epidemiol. 1993;  138 973-983
    Google Scholar
  • 5 Stamler J, Stamler R, Riedlinger WF, Algera G, Roberts RH. Hypertension screening of 1 million Americans. Community Hypertension Evaluation Clinic (CHEC) program, 1973 through 1975.  JAMA. 1976;  235 2299-2306
    Google Scholar
  • 6 Reckelhoff JF, Zhang H, Granger JP. Testosterone exacerbates hypertension and reduces pressure-natriuresis in male spontaneously hypertensive rats.  Hypertension. 1998;  31 435-439
    Google Scholar
  • 7 Reckelhoff JF, Zhang H, Srivastava K, Granger JP. Gender differences in hypertension in spontaneously hypertensive rats: role of androgens and androgen receptor.  Hypertension. 1999;  34 920-923
    Google Scholar
  • 8 Reckelhoff JF, Zhang H, Srivastava K. Gender differences in development of hypertension in spontaneously hypertensive rats: role of the renin-angiotensin system.  Hypertension. 2000;  35 480-483
    Google Scholar
  • 9 Jain L, Chen XJ, Ramosevac S, Brown LA, Eaton DC. Expression of highly selective sodium channels in alveolar type II cells is determined by culture conditions.  Am J Physiol Lung Cell Mol Physiol. 2001;  280 L646-L658
    Google Scholar
  • 10 Caulin-Glaser T, Garcia-Cardena G, Sarrel P, Sessa WC, Bender JR. 17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization.  Circ Res. 1997;  81 885-892
    Google Scholar
  • 11 Dubey RK, Jackson EK. Estrogen-induced cardiorenal protection: potential cellular, biochemical, and molecular mechanisms.  Am J Physiol Renal Physiol. 2001;  280 F365-F388
    Google Scholar
  • 12 Mulroney SE, Woda C, Johnson M, Pesce C. Gender differences in renal growth and function after uninephrectomy in adult rats.  Kidney Int. 1999;  56 944-953
    Google Scholar
  • 13 Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan MJ, Labarthe D. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988–1991.  Hypertension. 1995;  25 305-313
    Google Scholar
  • 14 Reckelhoff JF. Gender differences in the regulation of blood pressure.  Hypertension. 2001;  37 1199-1208
    Google Scholar
  • 15 Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, Rossier BC. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits.  Nature. 1994;  367 463-467
    Google Scholar
  • 16 Jasti J, Furukawa H, Gonzales EB, Gouaux E. Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH.  Nature. 2007;  449 316-323
    Google Scholar
  • 17 Schild L. The epithelial sodium channel: from molecule to disease.  Rev Physiol Biochem Pharmacol. 2004;  151 93-107
    Google Scholar
  • 18 Staub O, Abriel H, Plant P, Ishikawa T, Kanelis V, Saleki R, Horisberger JD, Schild L, Rotin D. Regulation of the epithelial Na+ channel by Nedd4 and ubiquitination.  Kidney Int. 2000;  57 809-815
    Google Scholar
  • 19 Fuller PJ, Brennan FE, Burgess JS. Acute differential regulation by corticosteroids of epithelial sodium channel subunit and Nedd4 mRNA levels in the distal colon.  Pflugers Arch. 2000;  441 94-101
    Google Scholar
  • 20 Masilamani S, Kim GH, Mitchell C, Wade JB, Knepper MA. Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney.  J Clin Invest. 1999;  104 R19-R23
    Google Scholar
  • 21 Renard S, Voilley N, Bassilana F, Lazdunski M, Barbry P. Localization and regulation by steroids of the alpha, beta and gamma subunits of the amiloride-sensitive Na+ channel in colon, lung and kidney.  Pflugers Arch. 1995;  430 299-307
    Google Scholar
  • 22 Loffing J, Zecevic M, Feraille E, Kaissling B, Asher C, Rossier BC, Firestone GL, Pearce D, Verrey F. Aldosterone induces rapid apical translocation of ENaC in early portion of renal collecting system: possible role of SGK.  Am J Physiol Renal Physiol. 2001;  280 F675-F682
    Google Scholar
  • 23 Pearce D, Kleyman TR. Salt, sodium channels, and SGK1.  J Clin Invest. 2007;  117 592-595
    Google Scholar
  • 24 Quinkler M, Bujalska IJ, Kaur K, Onyimba CU, Buhner S, Allolio B, Hughes SV, Hewison M, Stewart PM. Androgen receptor-mediated regulation of the alpha-subunit of the epithelial sodium channel in human kidney.  Hypertension. 2005;  46 787-798
    Google Scholar
  • 25 Song J, Hu X, Khan O, Tian Y, Verbalis JG, Ecelbarger CA. Increased blood pressure, aldosterone activity, and regional differences in renal ENaC protein during vasopressin escape.  Am J Physiol Renal Physiol. 2004;  287 F1076-F1083
    Google Scholar
  • 26 Racusen LC, Monteil C, Sgrignoli A, Lucskay M, Marouillat S, Rhim JG, Morin JP. Cell lines with extended in vitro growth potential from human renal proximal tubule: characterization, response to inducers, and comparison with established cell lines.  J Lab Clin Med. 1997;  129 318-329
    Google Scholar
  • 27 Bremner HR, Freywald T, O’Brodovich HM, Otulakowski G. Promoter analysis of the gene encoding the beta-subunit of the rat amiloride-sensitive epithelial sodium channel.  Am J Physiol Lung Cell Mol Physiol. 2002;  282 L124-L134
    Google Scholar
  • 28 Thomas CP, Auerbach SD, Zhang C, Stokes JB. The structure of the rat amiloride-sensitive epithelial sodium channel gamma subunit gene and functional analysis of its promoter.  Gene. 1999;  228 111-122
    Google Scholar
  • 29 Pelletier G. Localization of androgen and estrogen receptors in rat and primate tissues.  Histol Histopathol. 2000;  15 1261-1270
    Google Scholar
  • 30 Gambling L, Dunford S, Wilson CA, MacArdle HJ, Baines DL. Estrogen and progesterone regulate alpha, beta, and gammaENaC subunit mRNA levels in female rat kidney.  Kidney Int. 2004;  65 1774-1781
    Google Scholar
  • 31 Riazi S, Maric C, Ecelbarger CA. 17-beta Estradiol attenuates streptozotocin-induced diabetes and regulates the expression of renal sodium transporters.  Kidney Int. 2006;  69 471-480
    Google Scholar
  • 32 MacNicholas CM, Canessa CM. Diversity of channels generated by different combinations of epithelial sodium channel subunits.  J Gen Physiol. 1997;  109 681-692
    Google Scholar
  • 33 Knight KK, Wentzlaff DM, Snyder PM. Intracellular sodium regulates proteolytic activation of the epithelial sodium channel.  J Biol Chem. 2008;  283 27477-27482
    Google Scholar
  • 34 Quinkler M, Bumke-Vogt C, Meyer B, Bahr V, Oelkers W, Diederich S. The human kidney is a progesterone-metabolizing and androgen-producing organ.  J Clin Endocrinol Metab. 2003;  88 2803-2809
    Google Scholar
  • 35 Boulkroun S, Le Moellic C, Blot-Chabaud M, Farman N, Courtois-Coutry N. Expression of androgen receptor and androgen regulation of NDRG2 in the rat renal collecting duct.  Pflugers Arch. 2005;  451 388-394
    Google Scholar
  • 36 Kimura N, Mizokami A, Oonuma T, Sasano H, Nagura H. Immunocytochemical localization of androgen receptor with polyclonal antibody in paraffin-embedded human tissues.  J Histochem Cytochem. 1993;  41 671-678
    Google Scholar
  • 37 Quarmby VE, Yarbrough WG, Lubahn DB, French FS, Wilson EM. Autologous down-regulation of androgen receptor messenger ribonucleic acid.  Mol Endocrinol. 1990;  4 22-28
    Google Scholar
  • 38 Ing NH. Steroid hormones regulate gene expression posttranscriptionally by altering the stabilities of messenger RNAs.  Biol Reprod. 2005;  72 1290-1296
    Google Scholar
  • 39 Keller ET, Ershler WB, Chang C. The androgen receptor: a mediator of diverse responses.  Front Biosci. 1996;  1 d59-d71
    Google Scholar
  • 40 Prins GS, Woodham C. Autologous regulation of androgen receptor messenger ribonucleic acid in the separate lobes of the rat prostate gland.  Biol Reprod. 1995;  53 609-619
    Google Scholar
  • 41 Shan LX, Zhu LJ, Bardin CW, Hardy MP. Quantitative analysis of androgen receptor messenger ribonucleic acid in developing Leydig cells and Sertoli cells by in situ hybridization.  Endocrinology. 1995;  136 3856-3862
    Google Scholar
  • 42 Huhtaniemi IT, Pye SR, Limer KL, Thomson W, O’Neill TW, Platt H, Payne D, John SL, Jiang M, Boonen S, Borghs H, Vanderschueren D, Adams JE, Ward KA, Bartfai G, Casanueva F, Finn JD, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Silman AJ, Wu FC. Increased Estrogen Rather Than Decreased Androgen Action Is Associated with Longer Androgen Receptor CAG Repeats.  J Clin Endocrinol Metab. 2009;  94(1) 277-284
    Google Scholar

Correspondence

M. QuinklerMD 

Clinical Endocrinology

Department of Internal Medicine, Gastroenterology, Hepatology and Endocrinology Charité Campus Mitte

Charité Universitätsmedizin Berlin

Charitéplatz 1

10117 Berlin

Germany

Phone: +49/30/4505 142 59

Fax: +49/30/4505 149 58

Email: marcus.quinkler@charite.de

      >