Correction of proximal tubule phosphate transport defect in Hyp mice in vivo and in vitro with indomethacin

Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11098-103. doi: 10.1073/pnas.1834060100. Epub 2003 Sep 2.

Abstract

X-linked hypophosphatemia is the most prevalent inherited form of rickets. In this disorder, rickets results from hyperphosphaturia and inappropriately normal levels of 1,25(OH)2-vitamin D. Current therapy with oral phosphate and vitamin D improves the rickets, but has significant morbidity and does not significantly affect the short stature and hypophosphatemia. In the present study, we demonstrate that Hyp mice, which have a mutation homologous to that in patients with X-linked hypophosphatemia, have a 2-fold greater urinary prostaglandin E2 (PGE2) excretion than C57/B6 mice. To determine whether PGs were involved in the pathogenesis of this disorder, Hyp and C57/B6 mice received i.p. injections with vehicle or indomethacin (1 mg/kg of body weight twice daily for 4 days) and were studied approximately 12 h after the last dose of indomethacin. In the Hyp mice, indomethacin treatment decreased the fractional excretion of phosphate from 13.0 +/- 3.2% to 2.2 +/- 1.1% (P < 0.05), and increased serum phosphate from 2.9 +/- 0.2 mg/dl to 4.1 +/- 0.2 mg/dl (P < 0.05). There was no effect of indomethacin in C57/B6 mice. Indomethacin did not affect serum creatinine or inulin clearance, demonstrating that the normalization of urinary phosphate excretion was not caused by changes in glomerular filtration rate. Indomethacin treatment increased renal brush border membrane vesicle NaPi-2 protein abundance in Hyp mice to levels comparable to that of C57/B6 mice, but had no effect in C57/B6 mice. In vitro isolated perfused proximal tubule studies demonstrate directly that 10-6 M bath indomethacin normalized the phosphate transport defect in Hyp mice but had no effect on C57/B6 mice. In conclusion, there is dysregulation of renal PG metabolism in Hyp mice, and indomethacin treatment normalizes the urinary excretion of phosphate by a direct tubular effect.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biological Transport
  • Blotting, Western
  • Dinoprostone / urine
  • Electrophoresis, Polyacrylamide Gel
  • In Vitro Techniques
  • Indomethacin / pharmacology*
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphates / metabolism*

Substances

  • Phosphates
  • Dinoprostone
  • Indomethacin