Evidence of a Parathyroid Hormone-independent Chronic Effect of Estrogen on Renal Phosphate Handling and Sodium-dependent Phosphate Cotransporter Type IIa Expression

Abstract

The effects of estrogen on phosphate metabolism are not well understood. To better define the chronic effects of estrogen on phosphate balance and on renal phosphate handling, the following groups were examined: A. young male and female rats, age- and weight-matched (age 8–10 weeks, 1^st study), and B. ovariectomized female rats (OVX), 22 weeks old, ovariectomized aged-matched rats receiving estrogen replacement (15 μmol×3/week) for 14 weeks (OVX+E), control female rats (intact ovaries), and male rats, both age matched to OVX and OVX+E (2^nd Study). In younger females (1^st study), plasma phosphate was lower, whereas the urinary excretion of phosphate was higher than in males. In adult intact females and in OVX+E urinary excretion of phosphate was higher than in males and OVX (2^nd Study). In these rats, a significant correlation between plasma phosphate and estrogen level was found. Sodium-dependent phosphate cotransporter (NaPiIIa) mRNA expression and protein abundance were higher in the renal cortex of younger male rats than in age- and weight-matched females. In adult rats, NaPiIIa mRNA and protein abundance were higher in OVX than in OVX+E, and in mature males as compared with age-matched females. These differences were not related to the parathyroid hormone (PTH) levels. Chronic estrogen administration was also associated with increased plasma calcium level and urinary calcium excretion. These results suggest that chronic estrogen treatment is associated with an inhibitory, PTH-independent effect on the expression of NaPiIIa in the kidney, leading to sex-related differences in phosphate balance.

Key words

estrogen - urinary phosphate - plasma phosphate - NaPiIIa - urinary calcium

References

• 1 Mount DB, Yu ASL. Transport of inorganic solutes: sodium, chloride, potassium, magnesium, calcium and phosphate. In: Brenner & Rector's The Kidney Philadelphia: Saunders Elsevier, 8th ed; 2008: 156-213
• 2 Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS. Targeted inactivation of Npt2 in mice leads to severe phosphate wasting, hypercalciuria, and skeletal abnormalities.  Proc Natl Acad Sci USA. 1998;  95 5372-5377
• 3 Bergwitz C, Roslin NM, Tieder M, Loredo-Osti JC, Bastepe M, Abu-Zahra H, Frappier D, Burkett K, Carpenter TO, Anderson D, Garabedian M, Sermet I, Fujiwara TM, Morgan K, Tenenhouse HS, Juppner H. SLC3A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter Nap(i)-IIc in maintaining phosphate homeostasis.  Am J Hum Genet. 2006;  78 179-192
• 4 Forster IC, Hernando N, Biber J, Murer H. Proximal tubule handling of phosphate: A molecular perspective.  Kidney Int. 2006;  70 1548-1559
• 5 Fukumoto S, Yamashita T. FGF23 is a hormone-regulating phosphate metabolism-unique biological characteristics of FGF23.  Bone. 2007;  40 1190-1195
• 6 Farrow EG, Davis SI, Mooney SD, Beighton P, Mascarenhas L, Gutierrez YR, Pitukcheewanont P, White KE. Extended mutational analyses of FGFR1 in osteoglophonic dysplasia.  Am J Med Genet A.. 2006;  140 537-539
• 7 Nordin BEC, Smith DA. Diagnostic procedures in disorders of calcium metabolism. Boston: Little, Brown & Co; 1965: 14-15
• 8 Packer E, Holloway L, Newhall K, Kanwar G, Butterfield G, Marcus R. Effects of estrogen on daylong circulating calcium, phosphorus, 1,25-dihydroxyvitamin D, and parathyroid hormone in postmenopausal women.  J Bone Miner Res. 1990;  5 877-884
• 9 Dick IM, Devine A, Beilby J, Prince RL. Effects of endogenous estrogen on renal calcium and phosphate handling in elderly women.  Am Physiol Endocrinol Metab. 2005;  288 E430-E435
• 10 Dick IM, Prince RL. The effect of estrogen on renal phosphorus handling in the rat.  Am J Nephrol. 2001;  21 323-330
• 11 Beers KW, Thompson MA, Chini EN, Dousa TP. Beta-Estradiol inhibits Na+-P(i) cotransport across renal brush border membranes from ovariectomized rats.  Biochem Biophys Res Commun. 1996;  221 442-445
• 12 Han HJ, Lee YH, Park KM, Taub M. Estrdiol-17 beta stimulates phosphate uptake and is mitogenic for primary rabbit renal proximal tubule cells.  Exp Nephrol. 2002;  10 355-364
• 13 Riazi S, Maric C, Ecelbarger CA. 17 β-Estradiol attenuates streptozotocin-induced diabetes and regulates the expression of renal sodium transporters.  Kidney Int. 2006;  69 471-480
• 14 Faroqui S, Levi M, Soleimani M, Amlal H. Estrogen downregulates the proximal tubule type IIa sodium phosphate cotransporter causing phosphate wasting and hypophosphatemia.  Kidney Int. 2008;  73 141-1150
• 15 Lotinun S, Westerlind KC, Kennedy AM, Turner RT. Comparative effects of long-term continuous release of 16α-hydroxyestrone and 17β-estradiol on bone, uterus and serum cholesterol in ovariectomized adult rats.  Bone. 2003;  33 124-131
• 16 Xu X, Xiao JC, Luo LF, Wang S, Zhang JP, Huang JJ, Liu ML, Liu CG, Xu KQ, Li YJ, Song HP. Effects of ovariectomy and 17β-estradiol treatment on renin-angiotensin system, blood pressure and endothelial ultrastructure.  Int J Cardiol. 2008;  130 196-204
• 17 Lötscher M, Scarpetta Y, Levi M, Halaihel N, Wang H, Zajicek HK, Biber J, Mürer H, Kaissling B. Rapid downregulation of rat renal Na/Pi-cotransporter in response to parathyroid hormone involves microtubule rearrangement.  J Clin Invest. 1999;  104 483-494
• 18 Woda CB, Halaihel N, Wilson PV, Haramati A, Levi A, Mulroney SE. Regulation of renal NaPi-2 expression and tubular phosphate reabsorption by growth hormone in the juvenile rat.  Am J Physiol Renal Physiol. 2004;  287 F117-F123
• 19 Rubinger D, Wald H, Friedlaender MM, Silver J, Popovzer MM. Effect of intravenous glucagon on the urinary excretion of adenosine 3′5′-monophosphate in man and in rats. Evidence for activation of adenylate cyclase and formation of nephrogenous cyclic AMP.  Miner Electrolyte Metab. 1988;  14 211-220
• 20 Darling IM, Morris ME. Evaluation of true creatinine in rats reveals extensive renal secretion.  Pharm Res. 1991;  8 1318-1322
• 21 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
• 22 Prahbu S, Levi M, Dwarakanath V, Arar M, Biber J, Murer H, Baum M. Effect of glucocorticoids on neonatal rabbit renal cortical sodium-inorganic phosphate messenger RNA and protein abundance.  Pediatric Res. 1997;  41 20-24
• 23 Loffing J, Lotscher M, Kaissling B, Biber J, Murer H, Seikaly M, Alpern RJ, Levi M, Baum M, Moe OW. Renal Na/H exchanger NHE-3 and Na-PO₄ cotransporter NaP_i-2 protein expression in glucocorticoid excess and deficient states.  J Am Soc Nephrol. 1998;  9 1560-1567
• 24 Weinman EJ, Cunningham R, Wade JB, Shenolikar S. The role of NHERF-1 in the regulation of renal proximal tubule sodium-hydrogen exchanger 3 and sodium- dependent phosphate cotransporter 2a.  J Physiol. 2005;  567 27-32
• 25 Ediger TR, Kraus WL, Weinman EJ, Katznellenbogen BS. Estrogen receptor regulation of the Na/H regulatory factor.  Endocrinology. 1999;  40 2976-2982
• 26 Stemmer-Rachamimov AO, Wiederhold T, Nielsen GP, James M, Pinney- Michalowski D, Roy JE, Cohen WA, Ramesh V, Louis DN. NHE-RF, a merlin-interacting protein, is primarily expressed in luminal epithelia, proliferative endometrium, and estrogen receptor-positive breast carcinomas.  Am J Pathol. 2001;  158 57-62
• 27 Xu H, Uno JK, Inoue M, Xu L, Drees JB, Collins JF, Ghishan FK. Regulation of intestinal NaPi IIb cotransporter gene expression by estrogen.  Am J Physiol Gastrointest Liver Physiol. 2003;  285 G1317-G1324
• 28 Fujita M, Ogawa S, Tsukui T, Fufuoka H, Nemoto N, Tsutsumi O, Ouchi Y, Inue S. Differential expression of secreted frizzled-related protein 4 in decidual cells during pregnancy.  J Mol Endocrinol. 2002;  28 213-223
• 29 Shimada T, Urakawa I, Yamazaki Y, Hasegawa H, Hino R, Yoneya T, Tacheuchi Y, Fujita T, Fukumoto S, Yamashita T. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa.  Biochem Biophys Res Commun. 2004;  314 409-414
• 30 Berndt T, Kumar R. Phosphatonins and the regulation of phosphate homeostasis.  Annu Rev Physiol. 2007;  69 341-359
• 31 Ferrari SL, Bonjour JP, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men.  J Clin Endocrinol Metab. 2005;  90 1519-1524
• 32 Burnett-Bowie SM, Mendoza N, Lederer BZ. Effects of gonadal steroid withdrawal on serum phosphate and FGF-23 levels in men.  Bone. 2007;  40 913-918
• 33 Colin EM, Van Den Bemd GJ, Van Aken M, Christakos S, De Jonge HR, DeLuca HF, Prahl JM, Birkenhager JC, Buurman CJ, Pols HA, Van Leeuwen JP. Evidence for involvement of 17 beta-estrdiol in intestinal calcium absorption independent of 1, 25-dihydroxyvitamin D3 level in the rat.  J Bone Miner Res. 1999;  1 57-64
• 34 Van Cromhaut SJ, Rummens K, Stockmans I, Van Herck E, Dijcks FA, Ederveen AG, Carmeliet P, Verhaeghe J, Bouillon R, Carmeliet G. Intestinal calcium transporter genes are upregulated by estrogens and the reproductive cycle through vitamin D-receptor independent mechanisms.  J Bone Miner Res. 2003;  10 1725-1736
• 35 Choi KC, Jeung EB. Molecular mechanism of regulation of the calcium-binding protein calbindin-D (9 K), and its physiological role(s) in mammals: A review of current research.  J Cell Mol Med. 2008;  12 409-420
• 36 Van Abel M, Hoenderop J, Dardenne O, StArnaud A, Van Os CH, Van Leeuwen HJ, Bindels RJ. 1, 25-dihydroxyvitamin D (3)-independent stimulatory effect of estrogen on the expression of ECac1 in the kidney.  J Am Soc Nephrol. 2002;  13 2102-2109
• 37 Brunette MG, Leclerc M. Effect of estrogen on calcium and sodium transport by the nephron luminal membranes.  J Endocrinol. 2001;  170 441-450
• 38 Oz OK, Hajibeigi A, Howard K, Cummins CL, van Abel M, Bindels RJ, Word RA, Kuro-o M, Pak CY, Zerwekh JE. Aromatase deficiency causes altered expression of molecules critical for calcium reabsorption in the kidney of female mice.  J Bone Miner Res. 2007;  22 1893-1902
• 39 Torres PU, Prie D, Molina-Bletry V, Beck L, Silve C, Friedlander G. Klotho: an anti-aging protein involved in mineral and vitamin D metabolism.  Kidney Int. 2007;  71 730-737

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