Enhanced FGF23 serum concentrations and phosphaturia in gene targeted mice expressing WNK-resistant spak

Ganesh Pathare; Michael Föller; Diana Michael; Britta Walker; Michael Hierlmeier; Julia G. Mannheim; Bernd J. Pichler; Florian Lang

doi:10.1159/000343393

Enhanced FGF23 serum concentrations and phosphaturia in gene targeted mice expressing WNK-resistant spak

Ganesh Pathare, Michael Föller, Diana Michael, Britta Walker, Michael Hierlmeier, Julia G. Mannheim, Bernd J. Pichler, Florian Lang

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

36 Citations (Scopus)

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 spak^tg/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. © 2012 S. Karger AG, Basel.

Original language	English
Pages (from-to)	355-364
Journal	Kidney and Blood Pressure Research
Volume	36
Issue number	1
DOIs	https://doi.org/10.1159/000343393
Publication status	Published - 2012
Externally published	Yes

Bibliographical note

Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to <a href="mailto:[email protected]">[email protected]</a>.

Funding

The authors are indebted to Dario Alessi from the MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee, who kindly provided mice and the SPAK antibody. The authors are grateful to Maren Koenig for data acquisition and to Martin S. Judenhofer for valuable discussions. The authors further gratefully acknowledge the meticulous preparation of the manuscript by L. Subasic and M. Petrea. This work was supported by the Deutsche Forschungsgemeinschaft DFG.

Research Keywords

Bone density
FGF23
Na+
PHi
Phosphate cotransporter

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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 (spaktg/tg) and in mice expressing wild type SPAK (spakwt/wt). Results: Serum FGF23 level was significantly higher, urinary phosphate excretion significantly larger and serum phosphate concentration significantly lower in spaktg/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 spaktg/tg mice compared to spakwt/wt mice. Treatment of spakwt/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. {\textcopyright} 2012 S. Karger AG, Basel.",

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author = "Ganesh Pathare and Michael F{\"o}ller and Diana Michael and Britta Walker and Michael Hierlmeier and Mannheim, {Julia G.} and Pichler, {Bernd J.} and Florian Lang",

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T1 - Enhanced FGF23 serum concentrations and phosphaturia in gene targeted mice expressing WNK-resistant spak

AU - Pathare, Ganesh

AU - Föller, Michael

AU - Michael, Diana

AU - Walker, Britta

AU - Hierlmeier, Michael

AU - Mannheim, Julia G.

AU - Pichler, Bernd J.

AU - Lang, Florian

N1 - Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to <a href="mailto:[email protected]">[email protected]</a>.

PY - 2012

Y1 - 2012

N2 - 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 (spaktg/tg) and in mice expressing wild type SPAK (spakwt/wt). Results: Serum FGF23 level was significantly higher, urinary phosphate excretion significantly larger and serum phosphate concentration significantly lower in spaktg/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 spaktg/tg mice compared to spakwt/wt mice. Treatment of spakwt/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. © 2012 S. Karger AG, Basel.

AB - 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 (spaktg/tg) and in mice expressing wild type SPAK (spakwt/wt). Results: Serum FGF23 level was significantly higher, urinary phosphate excretion significantly larger and serum phosphate concentration significantly lower in spaktg/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 spaktg/tg mice compared to spakwt/wt mice. Treatment of spakwt/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. © 2012 S. Karger AG, Basel.

KW - Bone density

KW - FGF23

KW - Na+

KW - PHi

KW - Phosphate cotransporter

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DO - 10.1159/000343393

M3 - RGC 21 - Publication in refereed journal

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SN - 1420-4096

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EP - 364

JO - Kidney and Blood Pressure Research

JF - Kidney and Blood Pressure Research

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ER -

Enhanced FGF23 serum concentrations and phosphaturia in gene targeted mice expressing WNK-resistant spak

Abstract

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