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Calcineurin A Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Yulia Moz^*, Ronen Levi^*, Vardit Lavi-Moshayoff^*, Keith B. Cox, Jeffery D. Molkentin, Justin Silver^* and Tally Naveh-Many^*

*Minerva Center for Calcium and Bone Metabolism, Nephrology and Hypertension Services, The Hadassah Hebrew University Medical Center, Jerusalem, Israel; and Department of Pediatrics, University of Cincinnati, Children’s Hospital Medical Center, Cincinnati, Ohio

Correspondence to Dr. Tally Naveh-Many, Nephrology Services, Hadassah Hospital, P.O. Box 12000, Jerusalem Israel 91120. Phone: +972-2-6776789; Fax: +972-2-6421234; E-mail: tally{at}cc.huji.ac.il

The sensing and response to extracellular phosphate (Pi) concentration is preserved from prokaryotes to mammals and ensures an adequate supply of Pi in the face of large differences in its availability. In mammals, the kidneys are central to Pi homeostasis. Renal Pi reabsorption is mediated by a Na/Pi co-transporter that is regulated by a renal Pi sensing system and humoral factors. The signal transduction by which Pi regulates type II Na/Pi activity is largely unknown. It is shown that calcineurin inhibitors specifically and dramatically decrease type II Na/Pi gene expression in a proximal tubule cell line and in vivo. Mice with genetic deletion of the calcineurin A gene had a marked decrease in type II Na/Pi mRNA levels and remarkably did not show the expected increase in type II Na/Pi mRNA levels after the challenge of a low-Pi diet. In contrast, the regulation of renal 25(OH)-vitamin D 1-hydroxylase gene expression by Pi was intact. This is the first demonstration that calcineurin has a crucial role in the signal transduction pathway regulating renal Pi homeostasis both in vitro and in vivo. These results suggest that the use of calcineurin inhibitors contributes to the renal Pi wasting seen in renal transplant patients.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673