Vitamin D Receptor Controls Expression of the Anti-aging Klotho Gene in Mouse and Human Renal Cells

Overview

Journal Biochem Biophys Res Commun

Publisher Elsevier

Specialty Biochemistry

Date 2011 Oct 11

PMID 21982773

Citations 85

Authors

Ryan E Forster

Peter W Jurutka

Jui-Cheng Hsieh

Carol A Haussler

Christine L Lowmiller

Ichiro Kaneko

Mark R Haussler

G Kerr Whitfield

Affiliations

Soon will be listed here.

Abstract

Isoforms of the mammalian klotho protein serve as membrane co-receptors that regulate renal phosphate and calcium reabsorption. Phosphaturic effects of klotho are mediated in cooperation with fibroblast growth factor receptor-1 and its FGF23 ligand. The vitamin D receptor and its 1,25-dihydroxyvitamin D(3) ligand are also crucial for calcium and phosphate regulation at the kidney and participate in a feedback loop with FGF23 signaling. Herein we characterize vitamin D receptor-mediated regulation of klotho mRNA expression, including the identification of vitamin D responsive elements (VDREs) in the vicinity of both the mouse and human klotho genes. In keeping with other recent studies of vitamin D-regulated genes, multiple VDREs control klotho expression, with the most active elements located at some distance (-31 to -46 kb) from the klotho transcriptional start site. We therefore postulate that the mammalian klotho gene is up-regulated by liganded VDR via multiple remote VDREs. The phosphatemic actions of 1,25-dihydroxyvitamin D(3) are thus opposed via the combined phosphaturic effects of FGF23 and klotho, both of which are upregulated by the liganded vitamin D receptor.

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References

Diepens R, den Dekker E, Bens M, Weidema A, Vandewalle A, Bindels R . Characterization of a murine renal distal convoluted tubule cell line for the study of transcellular calcium transport. Am J Physiol Renal Physiol. 2003; 286(3):F483-9. DOI: 10.1152/ajprenal.00231.2003. View

Kolek O, Hines E, Jones M, LeSueur L, Lipko M, Kiela P . 1alpha,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol. 2005; 289(6):G1036-42. DOI: 10.1152/ajpgi.00243.2005. View

Mitobe M, Yoshida T, Sugiura H, Shirota S, Tsuchiya K, Nihei H . Oxidative stress decreases klotho expression in a mouse kidney cell line. Nephron Exp Nephrol. 2005; 101(2):e67-74. DOI: 10.1159/000086500. View

Kuro-O M . Klotho. Pflugers Arch. 2009; 459(2):333-43. DOI: 10.1007/s00424-009-0722-7. View

Seuter S, Vaisanen S, Radmark O, Carlberg C, Steinhilber D . Functional characterization of vitamin D responding regions in the human 5-Lipoxygenase gene. Biochim Biophys Acta. 2007; 1771(7):864-72. DOI: 10.1016/j.bbalip.2007.04.007. View

Chen C, Podvin S, Gillespie E, Leeman S, Abraham C . Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A. 2007; 104(50):19796-801. PMC: 2148378. DOI: 10.1073/pnas.0709805104. View

Cuddapah S, Jothi R, Schones D, Roh T, Cui K, Zhao K . Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. Genome Res. 2008; 19(1):24-32. PMC: 2612964. DOI: 10.1101/gr.082800.108. View

Haussler M, Haussler C, Whitfield G, Hsieh J, Thompson P, Barthel T . The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the "Fountain of Youth" to mediate healthful aging. J Steroid Biochem Mol Biol. 2010; 121(1-2):88-97. PMC: 2906618. DOI: 10.1016/j.jsbmb.2010.03.019. View

Hu M, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B . Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J. 2010; 24(9):3438-50. PMC: 2923354. DOI: 10.1096/fj.10-154765. View

10.

Kim S, Yamazaki M, Zella L, Shevde N, Pike J . Activation of receptor activator of NF-kappaB ligand gene expression by 1,25-dihydroxyvitamin D3 is mediated through multiple long-range enhancers. Mol Cell Biol. 2006; 26(17):6469-86. PMC: 1592822. DOI: 10.1128/MCB.00353-06. View

11.

Gattineni J, Twombley K, Goetz R, Mohammadi M, Baum M . Regulation of serum 1,25(OH)2 vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4. Am J Physiol Renal Physiol. 2011; 301(2):F371-7. PMC: 3154596. DOI: 10.1152/ajprenal.00740.2010. View

12.

Huang C . Regulation of ion channels by secreted Klotho: mechanisms and implications. Kidney Int. 2010; 77(10):855-60. DOI: 10.1038/ki.2010.73. View

13.

Hsieh J, Jurutka P, Nakajima S, Galligan M, Haussler C, Shimizu Y . Phosphorylation of the human vitamin D receptor by protein kinase C. Biochemical and functional evaluation of the serine 51 recognition site. J Biol Chem. 1993; 268(20):15118-26. View

14.

Meyer M, Watanuki M, Kim S, Shevde N, Pike J . The human transient receptor potential vanilloid type 6 distal promoter contains multiple vitamin D receptor binding sites that mediate activation by 1,25-dihydroxyvitamin D3 in intestinal cells. Mol Endocrinol. 2006; 20(6):1447-61. DOI: 10.1210/me.2006-0031. View

15.

Wang T, Tavera-Mendoza L, Laperriere D, Libby E, MacLeod N, Nagai Y . Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005; 19(11):2685-95. DOI: 10.1210/me.2005-0106. View

16.

Abramovitz L, Rubinek T, Ligumsky H, Bose S, Barshack I, Avivi C . KL1 internal repeat mediates klotho tumor suppressor activities and inhibits bFGF and IGF-I signaling in pancreatic cancer. Clin Cancer Res. 2011; 17(13):4254-66. DOI: 10.1158/1078-0432.CCR-10-2749. View

17.

MacDonald P, Dowd D, Nakajima S, Galligan M, Reeder M, Haussler C . Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene. Mol Cell Biol. 1993; 13(9):5907-17. PMC: 360339. DOI: 10.1128/mcb.13.9.5907-5917.1993. View

18.

Weth O, Weth C, Bartkuhn M, Leers J, Uhle F, Renkawitz R . Modular insulators: genome wide search for composite CTCF/thyroid hormone receptor binding sites. PLoS One. 2010; 5(4):e10119. PMC: 2852416. DOI: 10.1371/journal.pone.0010119. View

19.

Shiraki-Iida T, Aizawa H, Matsumura Y, Sekine S, Iida A, Anazawa H . Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett. 1998; 424(1-2):6-10. DOI: 10.1016/s0014-5793(98)00127-6. View

20.

Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T . Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997; 390(6655):45-51. DOI: 10.1038/36285. View