Coordinated Control of Renal Ca(2+) Transport Proteins by Parathyroid Hormone

Kidney Int. 2005 Oct;68(4):1708-21. doi: 10.1111/j.1523-1755.2005.00587.x.

Abstract

Background: The kidney is one of the affected organs involved in the clinical symptoms of parathyroid hormone (PTH)-related disorders, like primary hyperparathyroidism and familial hypocalciuric hypercalcemia. The molecular mechanism(s) underlying alterations in renal Ca(2+) handling in these disorders is poorly understood.

Methods: Parathyroidectomized and PTH-supplemented rats and mice infused with the calcimimetic compound NPS R-467 were used to study the in vivo effect of PTH on the expression of renal transcellular Ca(2+) transport proteins, including the epithelial Ca(2+) channel transient receptor potential, vanilloid, member 5 (TRPV5), calbindins, and the Na(+)/Ca(2+)-exchanger (NCX1). In addition, the effect of PTH on transepithelial Ca(2+) transport in rabbit connecting tubule/cortical collecting duct (CNT/CCD) primary cultures was determined.

Results: Decreased PTH levels in parathyroidectomized rats or NPS R-467-infused mice, resulted in reduced expression of these proteins, which is consistent with diminished Ca(2+) reabsorption, causing the development of the observed hypocalcemia. PTH supplementation of parathyroidectomized rats restored the expression of the renal Ca(2+) transport machinery and serum Ca(2+) levels, independent of serum 1,25-dihydroxyvitamin D(3) levels and renal vitamin D or Ca(2+)-sensing receptor mRNA abundance. Inhibition of the PTH-stimulated transepithelial Ca(2+) transport by the TRPV5-specific inhibitor ruthenium red reduced the PTH-stimulated expression of calbindin-D(28K) and NCX1 in rabbit CNT/CCD primary cultures.

Conclusion: PTH stimulates renal Ca(2+) reabsorption through the coordinated expression of renal transcellular Ca(2+) transport proteins. Moreover, the PTH-induced stimulation is enhanced by the magnitude of the Ca(2+) influx through the gatekeeper TRPV5, which in turn facilitates the expression of the downstream Ca(2+) transport proteins. Therefore, the renal transcellular Ca(2+) transport proteins, including TRPV5, could contribute to the pathogenesis of PTH-related disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology
  • Animals
  • Calbindins
  • Calcium / agonists
  • Calcium / metabolism*
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Cells, Cultured
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gene Expression
  • Hypocalcemia / drug therapy
  • Hypocalcemia / metabolism
  • Hypocalcemia / physiopathology
  • Kidney / cytology
  • Kidney / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Parathyroid Hormone / blood
  • Parathyroid Hormone / pharmacology
  • Parathyroid Hormone / physiology*
  • Parathyroidectomy
  • Rabbits
  • Rats
  • Rats, Inbred Strains
  • Receptors, Calcium-Sensing / genetics
  • Receptors, Calcium-Sensing / metabolism
  • S100 Calcium Binding Protein G / genetics
  • S100 Calcium Binding Protein G / metabolism
  • Sodium-Calcium Exchanger / genetics
  • Sodium-Calcium Exchanger / metabolism
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*

Substances

  • Aniline Compounds
  • Calbindins
  • Calcium Channels
  • NPS R-467
  • Parathyroid Hormone
  • Receptors, Calcium-Sensing
  • S100 Calcium Binding Protein G
  • Sodium-Calcium Exchanger
  • TRPV Cation Channels
  • TRPV5 protein, rat
  • sodium-calcium exchanger 1
  • Calcium