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J. Biol. Chem., Vol. 283, Issue 1, 175-183, January 4, 2008

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Extracellular Calcium-sensing Receptor Activation Induces Vitamin D Receptor Levels in Proximal Kidney HK-2G Cells by a Mechanism That Requires Phosphorylation of p38 MAPK^*

Aparna Maiti, Nitai C. Hait, and Matthew J. Beckman¹

From the Departments of Orthopaedic Surgery and Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia 23298-0164

In hypocalcaemia, elevated parathyroid hormone transitorily down-regulates the kidney vitamin D receptor, which returns to normal levels with the rise in serum extracellular calcium [Ca²⁺]_e. In this study, we investigated the mechanism that underlies VDR increase in kidney in association with elevated [Ca²⁺]_e. Examination of MAP kinase signals in a proximal tubule human kidney (HK-2G) epithelial cell line showed that treatment of [Ca²⁺]_e in the culture medium elevated phosphorylation of both ERK and p38 MAPKs. Blockade of p38 phosphorylation with SB203580 or SB202190 in turn abolished [Ca²⁺]_e-mediated VDR protein increase, while treatment with PD98059 and U0126, specifically blocked ERK phosphorylation, but had no effect on VDR stimulation by [Ca²⁺]_e. Furthermore, SB203580 treatment potently repressed [Ca²⁺]_e-mediated activation of VDR promoter. We also demonstrate that si-RNA knock down of p38 completely diminished high [Ca²⁺]_e-mediated VDR induction. Direct CaSR involvement was demonstrated by using an si-RNA of CaSR that impeded [Ca²⁺]_e-mediated induction of VDR. In conclusion, a high extracellular [Ca²⁺]_e concentration in the physiological range is capable of directly increasing renal proximal VDR expression, and the induction mechanism requires activation of the CaSR and signal mediation by the p38 MAP kinase pathway.

Received for publication, August 30, 2007 , and in revised form, October 31, 2007.

^* The work was supported in part by a USDA Specific Cooperative Agreement (SCA 58-3625-6-103), and by the VCU Dept. of Orthopaedic Surgery. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, VA Commonwealth University, 1112 E. Clay St., Richmond, VA 23298. Tel.: 804-628-0225; Fax: 804-828-1532; E-mail: mjbeckma{at}vcu.edu.

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