Advertisement

Pflügers Archiv

, Volume 452, Issue 4, pp 444–452 | Cite as

Renal Ca2+ handling in sgk1 knockout mice

  • Diana Sandulache
  • Florian Grahammer
  • Ferruh Artunc
  • Guido Henke
  • Azeemudeen Hussain
  • Omaima Nasir
  • Andreas Mack
  • Björn Friedrich
  • Volker Vallon
  • Peer Wulff
  • Dietmar Kuhl
  • Monica Palmada
  • Florian LangEmail author
Renal Function, Body Fluids

Abstract

Coexpression studies in Xenopus oocytes revealed the ability of the serum- and glucocorticoid-inducible kinase 1 (SGK1) to stimulate the renal epithelial Ca2+ channel TRPV5. SGK1 increases the abundance of the channel protein in the plasma membrane, an effect requiring the participation of the Na+/H+ exchanger regulating factor 2 (NHERF2). The present study was performed to explore the role of SGK1 in the regulation of renal Ca2+ handling in vivo. To this end, TRPV5, calbindin D-28K abundance, and renal Ca2+ excretion were analyzed in gene-targeted mice lacking functional SGK1 (sgk1 −/− ) and their age- and sex-matched littermates (sgk1 +/+ ). Immunohistochemistry revealed lower abundance of TRPV5 and calbindin D-28K protein in sgk1 −/− mice than in sgk1 +/+ mice, both fed with control diet. Feeding the mice a Ca2+-deficient diet marked ly increased TRPV5 protein abundance in both genotypes. Renal Ca2+ excretion under control diet was significantly lower in sgk1 −/− than in sgk1 +/+ mice. The Ca2+-deficient diet decreased renal excretion of Ca2+ to the same levels in both phenotypes. Furosemide increased fractional Ca2+ excretion and dissipated the difference between phenotypes. We conclude that lack of SGK1 may lead to decrease in TRPV5 abundance in connecting tubules but does not abrogate TRPV5 regulation. The decrease in abundance of TRPV5 in connecting tubules of sgk1 −/− mice is presumably compensated for by enhanced Ca2+ reabsorption in upstream nephron segments such as the loop of Henle, which may indirectly result from impaired SGK1-dependent Na+ reabsorption in the aldosterone-sensitive distal part of the nephron, salt loss, and enhanced Na+ (and Ca2+) reabsorption in those upstream nephron segments.

Keywords

TRPV5 ECaC Calciuria Calcium Kidney Proximal tubule Henle loop 

Notes

Acknowledgements

This work was supported by grants from DFG and BMBF (F.L. and V.V.) and the DAAD (O.N.).

References

  1. 1.
    Akutsu N, Lin R, Bastien Y, Bestawros A, Enepekides DJ, Black MJ, White JH (2001) Regulation of gene expression by 1alpha,25-dihydroxyvitamin D3 and its analog EB1089 under growth-inhibitory conditions in squamous carcinoma cells. Mol Endocrinol 15:1127–1139PubMedCrossRefGoogle Scholar
  2. 2.
    Alessi DR, Cohen P (1998) Mechanism of activation and function of protein kinase B. Curr Opin Genet Dev 8:55–62PubMedCrossRefGoogle Scholar
  3. 3.
    Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15:6541–6551PubMedGoogle Scholar
  4. 4.
    Chen SY, Bhargava A, Mastroberardino L, Meijer OC, Wang J, Buse P, Firestone GL, Verrey F, Pearce D (1999) Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc Natl Acad Sci U S A 96:2514–2519PubMedCrossRefGoogle Scholar
  5. 5.
    Divecha N, Banfic H, Irvine RF (1991) The polyphosphoinositide cycle exists in the nuclei of Swiss 3T3 cells under the control of a receptor (for IGF-I) in the plasma membrane, and stimulation of the cycle increases nuclear diacylglycerol and apparently induces translocation of protein kinase C to the nucleus. EMBO J 10:3207–3214PubMedGoogle Scholar
  6. 6.
    Embark HM, Setiawan I, Poppendieck S, van de Graaf SFJ, Boehmer C, Palmada M, Wieder T, Gerstberger R, Cohen P, Yun CC, Bindels RJM, Lang F (2004) Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms SGK1 and SGK3 expressed in Xenopus oocytes. Cell Physiol Biochem 14:203–212PubMedCrossRefGoogle Scholar
  7. 7.
    Firestone GL, Giampaolo JR, O’Keeffe BA (2003) Stimulus-dependent regulation of the serum and glucocorticoid inducible protein kinase (Sgk) transcription, subcellular localization and enzymatic activity. Cell Physiol Biochem 13:1–12PubMedCrossRefGoogle Scholar
  8. 8.
    Friedman PA, Gesek FA (1995) Cellular calcium transport in renal epithelia: measurement, mechanisms, and regulation. Physiol Rev 75:429–471PubMedGoogle Scholar
  9. 9.
    Gamper N, Fillon S, Huber SM, Feng Y, Kobayashi T, Cohen P, Lang F (2002) IGF-1 up-regulates K+ channels via PI3-kinase, PDK1 and SGK1. Pflugers Arch 443:625–634PubMedCrossRefGoogle Scholar
  10. 10.
    Hoenderop JG, Dardenne O, Van Abel M, Van Der Kemp AW, van Os CH, Arnaud R, Bindels RJ (2002) Modulation of renal Ca2+ transport protein genes by dietary Ca2+ and 1,25-dihydroxyvitamin D3 in 25-hydroxyvitamin D3-1alpha-hydroxylase knockout mice. FASEB J 16:1398–1406PubMedCrossRefGoogle Scholar
  11. 11.
    Hoenderop JG, Muller D, Suzuki M, van Os CH, Bindels RJ (2000) Epithelial calcium channel: gate-keeper of active calcium reabsorption. Curr Opin Nephrol Hypertens 9:335–340PubMedCrossRefGoogle Scholar
  12. 12.
    Hoenderop JG, Nilius B, Bindels RJ (2002) Molecular mechanism of active Ca2+ reabsorption in the distal nephron. Annu Rev Physiol 64:529–549PubMedCrossRefGoogle Scholar
  13. 13.
    Hoenderop JG, Van Der Kemp AW, Hartog A, van de Graaf SF, van Os CH, Willems PH, Bindels RJ (1999) Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D3-responsive epithelia. J Biol Chem 274:8375–8378PubMedCrossRefGoogle Scholar
  14. 14.
    Hoenderop JG, Van Der Kemp AW, Hartog A, van Os CH, Willems PH, Bindels RJ (1999) The epithelial calcium channel, ECaC, is activated by hyperpolarization and regulated by cytosolic calcium. Biochem Biophys Res Commun 261:488–492PubMedCrossRefGoogle Scholar
  15. 15.
    Hoenderop JG, Willems PH, Bindels RJ (2000) Toward a comprehensive molecular model of active calcium reabsorption. Am J Physiol Renal Physiol 278:F352–F360PubMedGoogle Scholar
  16. 16.
    Huang DY, Wulff P, Volkl H, Loffing J, Richter K, Kuhl D, Lang F, Vallon V (2004) Impaired regulation of renal K+ elimination in the sgk1-knockout mouse. J Am Soc Nephrol 15:885–891PubMedCrossRefGoogle Scholar
  17. 17.
    Kobayashi T, Cohen P (1999) Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem J 339:319–328PubMedCrossRefGoogle Scholar
  18. 18.
    Kotani K, Yonezawa K, Hara K, Ueda H, Kitamura Y, Sakaue H, Ando A, Chavanieu A, Calas B, Grigorescu F et al (1994) Involvement of phosphoinositide 3-kinase in insulin- or IGF-1-induced membrane ruffling. EMBO J 13:2313–2321PubMedGoogle Scholar
  19. 19.
    Mery L, Strauss B, Dufour JF, Krause KH, Hoth M (2002) The PDZ-interacting domain of TRPC4 controls its localization and surface expression in HEK293 cells. J Cell Sci 115:3497–3508PubMedGoogle Scholar
  20. 20.
    Naray-Fejes-Toth A, Canessa C, Cleaveland ES, Aldrich G, Fejes-Toth G (1999) Sgk is an aldosterone-induced kinase in the renal collecting duct. Effects on epithelial Na+ channels. J Biol Chem 274:16973–16978PubMedCrossRefGoogle Scholar
  21. 21.
    Palmada M, Poppendieck S, Embark HM, van de Graaf SF, Boehmer C, Bindels RJ, Lang F (2005) Requirement of PDZ domains for the stimulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase SGK1. Cell Physiol Biochem 15:175–182PubMedCrossRefGoogle Scholar
  22. 22.
    Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA (1999) Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J 18:3024–3033PubMedCrossRefGoogle Scholar
  23. 23.
    Pearce D (2003) SGK1 regulation of epithelial sodium transport. Cell Physiol Biochem 13:13–20PubMedCrossRefGoogle Scholar
  24. 24.
    Shenolikar S, Weinman EJ (2001) NHERF: targeting and trafficking membrane proteins. Am J Physiol Renal Physiol 280:F389–F395PubMedGoogle Scholar
  25. 25.
    Shigaev A, Asher C, Latter H, Garty H, Reuveny E (2000) Regulation of sgk by aldosterone and its effects on the epithelial Na(+) channel. Am J Physiol Renal Physiol 278:F613–F619PubMedGoogle Scholar
  26. 26.
    Vallon V (2003) In vivo studies of the genetically modified mouse kidney. Nephron Physiol 94:1–5CrossRefGoogle Scholar
  27. 27.
    Verrey F, Loffing J, Zecevic M, Heitzmann D, Staub O (2003) SGK1: aldosterone-induced relay of Na+ transport regulation in distal kidney nephron cells. Cell Physiol Biochem 13:21–28PubMedCrossRefGoogle Scholar
  28. 28.
    Webster MK, Goya L, Firestone GL (1993) Immediate-early transcriptional regulation and rapid mRNA turnover of a putative serine/threonine protein kinase. J Biol Chem 268:11482–11485PubMedGoogle Scholar
  29. 29.
    Webster MK, Goya L, Ge Y, Maiyar AC, Firestone GL (1993) Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. Mol Cell Biol 13:2031–2040PubMedGoogle Scholar
  30. 30.
    Weinman EJ, Steplock D, Wang Y, Shenolikar S (1995) Characterization of a protein cofactor that mediates protein kinase A regulation of the renal brush border membrane Na(+)–H+ exchanger. J Clin Invest 95:2143–2149PubMedCrossRefGoogle Scholar
  31. 31.
    Wulff P, Vallon V, Huang DY, Volkl H, Yu F, Richter K, Jansen M, Schlunz M, Klingel K, Loffing J, Kauselmann G, Bosl MR, Lang F, Kuhl D (2002) Impaired renal Na(+) retention in the sgk1-knockout mouse. J Clin Invest 110:1263–1268PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Diana Sandulache
    • 1
  • Florian Grahammer
    • 1
  • Ferruh Artunc
    • 1
  • Guido Henke
    • 1
  • Azeemudeen Hussain
    • 1
  • Omaima Nasir
    • 1
  • Andreas Mack
    • 2
  • Björn Friedrich
    • 3
  • Volker Vallon
    • 4
  • Peer Wulff
    • 5
  • Dietmar Kuhl
    • 6
  • Monica Palmada
    • 1
  • Florian Lang
    • 1
    Email author
  1. 1.Department of PhysiologyUniversity of TübingenTübingenGermany
  2. 2.Department of AnatomyUniversity of TübingenTübingenGermany
  3. 3.Department of Internal MedicineUniversity of TübingenTübingenGermany
  4. 4.Departments of Medicine and PharmacologyUniversity of CaliforniaSan DiegoUSA
  5. 5.Department of Clinical NeurobiologyUniversity of HeidelbergHeidelbergGermany
  6. 6.Department of Biology, Chemistry, and PharmacyFree University BerlinBerlinGermany

Personalised recommendations