Renal Ca2+ handling in sgk1 knockout mice
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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.
KeywordsTRPV5 ECaC Calciuria Calcium Kidney Proximal tubule Henle loop
This work was supported by grants from DFG and BMBF (F.L. and V.V.) and the DAAD (O.N.).
- 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.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
- 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