1,25-dihydroxyvitamin D(3)-independent stimulatory effect of estrogen on the expression of ECaC1 in the kidney.
Estrogen deficiency results in a negative Ca(2+) balance and bone loss in postmenopausal women. In addition to bone, the intestine and kidney are potential sites for estrogen action and are involved in Ca(2+) handling and regulation. The epithelial Ca(2+) channel ECaC1 (or TRPV5) is the entry channel involved in active Ca(2+) transport. Ca(2+) entry is followed by cytosolic diffusion, facilitated by calbindin-D(28K) and/or calbindin-D(9k), and active extrusion across the basolateral membrane by the Na(+)/Ca(2+)-exchanger (NCX1) and plasma membrane Ca(2+)-ATPase (PMCA1b). In this transcellular Ca(2+) transport, ECaC1 probably represents the final regulatory target for hormonal control. The aim of this study was to determine whether 17beta-estradiol (17beta-E(2)) is involved in Ca(2+) reabsorption via regulation of the expression of ECaC1. The ovariectomized rat model was used to investigate the regulation of ECaC1, at the mRNA and protein levels, by 17beta-E(2) replacement therapy. Using real-time quantitative PCR and immunohistochemical analyses, this study demonstrated that 17beta-E(2) treatment at pharmacologic doses increased renal mRNA levels of ECaC1, calbindin-D(28K), NCX1, and PMCA1b and increased the protein abundance of ECaC1. Furthermore, the involvement of 1,25-dihydroxyvitamin D(3) in the effects of 17beta-E(2) was examined in 25-hydroxyvitamin D(3)-1alpha-hydroxylase-knockout mice. Renal mRNA expression of calbindin-D(9K), calbindin-D(28K), NCX1, and PMCA1b was not significantly altered after 17beta-E(2) treatment. In contrast, ECaC1 mRNA and protein levels were both significantly upregulated. Moreover, 17beta-E(2) treatment partially restored serum Ca(2+) levels, from 1.63 +/- 0.06 to 2.03 +/- 0.12 mM. In conclusion, this study suggests that 17beta-E(2) is positively involved in renal Ca(2+) reabsorption via the upregulation of ECaC1, an effect independent of 1,25-dihydroxyvitamin D(3).
Department of Cell Physiology, Nijmegen Center for Molecular Life Sciences, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Monique
M
Van Abel
Joost G J
JG
Hoenderop
Olivier
O
Dardenne
René
R
St  Arnaud
Carel H
CH
Van Os
Hans J P T M
HJ
Van Leeuwen
René J M
RJ
Bindels
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000172:deficiency / Q000235:genetics; D000042:Absorption / Q000187:drug effects; D000818:Animals; D002117:Calcitriol / Q000172:deficiency / Q000502:physiology*; D002118:Calcium / Q000097:blood; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050916:TRPV Cation Channels; D015854:Up-Regulation
D015220:Calcium Channels; D012333:RNA, Messenger; D050916:TRPV Cation Channels; C492241:TRPV5 protein, rat; C492240:Trpv5 protein, mouse; D004958:Estradiol; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002118:Calcium