title: Enhanced FGF23 serum concentrations and phosphaturia in gene targeted mice expressing WNK-resistant SPAK.
abstract: BACKGROUND
  The WNK-dependent STE20/SPS1-related proline/alanine-rich kinase (SPAK) regulates the renal thiazide sensitive NaCl cotransporter (NCC) and the renal furosemide sensitive Na+, K+, 2Cl- cotransporter (NKCC2) and thus participates in the regulation of renal salt excretion, extracellular fluid volume and blood pressure. Inhibition of NCC leads to anticalciuria. Moreover, NCC is also expressed in osteoblasts where it is implicated in the regulation of bone mineralization. Osteoblasts further influence mineral metabolism by releasing the phosphaturic hormone FGF23. The present study explored, whether SPAK participates in the regulation of calcium-phosphate homeostasis.
  
  
  METHODS
  FGF23 serum levels and phosphate homeostasis were analyzed in gene targeted mice expressing SPAK resistant to WNK-dependent activation (spak(tg/tg)) and in mice expressing wild type SPAK (spak(wt/wt)).
  
  
  RESULTS
  Serum FGF23 level was significantly higher, urinary phosphate excretion significantly larger and serum phosphate concentration significantly lower in spak(tg/tg) mice than in spak(wt/wt) mice. Urinary calcium excretion was significantly decreased in spaktg/tg mice. Serum levels of calcitriol and PTH were not significantly different between the genotypes. Bone density was significantly increased in spak(tg/tg) mice compared to spak(wt/wt) mice. Treatment of spak(wt/wt) mice with HCT increased FGF23 serum levels, and led to phosphaturia and hypophosphatemia.
  
  
  CONCLUSIONS
  SPAK is a strong regulator of FGF23 formation, bone mineralization and renal Ca2+ and phosphate excretion.
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Pathare
authors.forename: Michael
authors.initials: M
authors.lastname: Föller
authors.forename: Diana
authors.initials: D
authors.lastname: Michael
authors.forename: Britta
authors.initials: B
authors.lastname: Walker
authors.forename: Michael
authors.initials: M
authors.lastname: Hierlmeier
authors.forename: Julia G
authors.initials: JG
authors.lastname: Mannheim
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D055879:Gene Knock-In Techniques; D006706:Homeostasis / Q000502:physiology; D007015:Hypophosphatemia, Familial / Q000453:epidemiology / Q000378:metabolism*; D015994:Incidence; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D015778:Minor Histocompatibility Antigens; D023421:Models, Animal; D010710:Phosphates / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: C000717428:Fgf23 protein, mouse; D015778:Minor Histocompatibility Antigens; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498744:Wnk1 protein, mouse; D002118:Calcium