X-linked hypophosphatemia is characterized by renal phosphate wasting resulting in hypophosphatemia, and a relative deficiency of 1,25(OH)2 vitamin D. These defects are thought to be due to increased levels of a circulating phosphatonin, FGF-23. Current therapy includes administration of oral phosphate and 1,25(OH)2 vitamin D which results in improvement of rickets but can result in hyperparathyroidism, hypercalcemia, hypercalciuria and nephrocalcinosis. We have found that the Hyp mouse, which has the same genetic defect as humans with X-linked hypophosphatemia, has a higher rate of urinary prostaglandin excretion and proximal tubule PGE2 content than C57/B6 mice. Indomethacin administration in vivo and in vitro totally normalizes the hyperphosphaturia, the transport defect in isolated perfused tubules and NaPi co-transporter abundance in brush border membrane vesicles. In addition we find that the phosphate transport defect and the paucity of NaPi transporters in Hyp mice are reversible within an hour of incubation in vitro suggesting rapid phosphatonin washout. We demonstrate that luminal addition of FGF-23 inhibits phosphate transport in the mouse and rabbit proximal tubule.
The first Aim of this proposal is to characterize how the putative phosphatonin, FGF-23, inhibits phosphate transport in isolated perfused mouse proximal tubules.
The second Aim i s to determine the role of PGE2 in the regulation of proximal tubule phosphate transport in X-linked hypophosphatemia.
The third Aim i s to determine the role of abnormal prostaglandin production in the pathogenesis of the bone and renal abnormalities in Hyp mice. We will examine if chronic indomethacin therapy, which we find increases serum phosphate in Hyp mice, improves their bone disease, growth and abnormal vitamin D metabolism. These studies will not only examine the pathogenesis of this disorder, but will directly examine if indomethacin potentially represents a novel therapy for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK065842-01A1
Application #
6863584
Study Section
Special Emphasis Panel (ZRG1-RUS-D (03))
Program Officer
Ketchum, Christian J
Project Start
2005-03-01
Project End
2008-02-29
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
1
Fiscal Year
2005
Total Cost
$234,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Gattineni, Jyothsna; Baum, Michel (2010) Regulation of phosphate transport by fibroblast growth factor 23 (FGF23): implications for disorders of phosphate metabolism. Pediatr Nephrol 25:591-601
Gattineni, Jyothsna; Bates, Carlton; Twombley, Katherine et al. (2009) FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 297:F282-91
Seikaly, Mouin G; Waber, Pamela G; Baum, Michel (2008) Urinary prostaglandins and the effect of indomethacin on phosphate excretion in children with hypophosphatemic rickets. Pediatr Res 64:210-2
Baum, Michel; Syal, Ashu; Quigley, Raymond et al. (2006) Role of prostaglandins in the pathogenesis of X-linked hypophosphatemia. Pediatr Nephrol 21:1067-74
Syal, Ashu; Schiavi, Susan; Chakravarty, Sumana et al. (2006) Fibroblast growth factor-23 increases mouse PGE2 production in vivo and in vitro. Am J Physiol Renal Physiol 290:F450-5
Kurosu, Hiroshi; Ogawa, Yasushi; Miyoshi, Masayoshi et al. (2006) Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281:6120-3