Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway.
Aldosterone regulates volume homeostasis and blood pressure by enhancing sodium reabsorption in the kidney's distal nephron (DN). On the apical surface of these renal epithelia, aldosterone increases expression and activity of the thiazide-sensitive Na-Cl cotransporter (NCC) and the epithelial sodium channel (ENaC). While the cellular mechanisms by which aldosterone regulates ENaC have been well characterized, the molecular mechanisms that link aldosterone to NCC-mediated Na+/Cl- reabsorption remain elusive. The serine/threonine kinase with-no-lysine 4 (WNK4) has previously been shown to reduce cell surface expression of NCC. Here we measured sodium uptake in a Xenopus oocyte expression system and found that serum and glucocorticoid-induced kinase 1 (SGK1), an aldosterone-responsive gene expressed in the DN, attenuated the inhibitory effect of WNK4 on NCC activity. In addition, we showed--both in vitro and in a human kidney cell line--that SGK1 bound and phosphorylated WNK4. We found one serine located within an established SGK1 consensus target sequence, and the other within a motif that was, to our knowledge, previously uncharacterized. Mutation of these target serines to aspartate, in order to mimic phosphorylation, attenuated the effect of WNK4 on NCC activity in the Xenopus oocyte system. These data thus delineate what we believe to be a novel mechanism for aldosterone activation of NCC through SGK1 signaling of WNK4 kinase.
Rozansky
David J
DJ
Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA.
Cornwall
Tonya
T
Subramanya
Arohan R
AR
Rogers
Shaunessy
S
Yang
Yong-Feng
YF
David
Larry L
LL
Zhu
Xiaoman
X
Yang
Chao-Ling
CL
Ellison
David H
DH
D000450:Aldosterone / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011955:Receptors, Drug / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D049992:Sodium Chloride Symporters / Q000378:metabolism*; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000378:metabolism; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
D000450:Aldosterone; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D011955:Receptors, Drug; D011993:Recombinant Fusion Proteins; D012964:Sodium; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D000099184:Serum-Glucocorticoid Regulated Kinases; C578874:SLC12A3 protein, human; C064415:thiazide receptor; C499024:Prkwnk4 protein, mouse; C433806:WNK4 protein, human
Sci STKE. 2001 Nov 13;2001(108):re17
11707620
Physiol Rev. 2000 Jan;80(1):277-313
10617770
J Clin Invest. 2003 Apr;111(7):1039-45
12671053
Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14552-7
9826738
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2514-9
10051674
Am J Physiol Renal Physiol. 2009 Sep;297(3):F685-92
19587141
Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):680-4
12515852
J Clin Invest. 2007 Mar;117(3):592-5
17332888
Am J Physiol Renal Physiol. 2008 Oct;295(4):F1199-206
18701621
J Biol Chem. 2005 Feb 11;280(6):4518-23
15576372
Cell Physiol Biochem. 2003;13(1):21-8
12649599
Hypertension. 2002 Sep;40(3):256-60
12215463
Proc Natl Acad Sci U S A. 2009 May 12;106(19):7804-9
19380724
J Clin Invest. 2007 Nov;117(11):3403-11
17975670
Trends Endocrinol Metab. 2005 Apr;16(3):98-103
15808806
Oncogene. 2001 Sep 6;20(39):5562-9
11571656
J Biol Chem. 2009 Jul 3;284(27):18471-80
19401467
Am J Physiol Renal Physiol. 2008 Jun;294(6):F1298-305
18385268
Exp Mol Med. 2007 Oct 31;39(5):565-73
18059132
Kidney Int. 2005 Nov;68(5):2164-72
16221215
Pflugers Arch. 2009 May;458(1):157-68
18839206
Mol Endocrinol. 2005 Dec;19(12):3073-84
16099816
Am J Physiol. 1996 Jan;270(1 Pt 2):F211-9
8769842
J Biol Chem. 2000 Jun 2;275(22):16795-801
10828064
J Biol Chem. 2002 Dec 13;277(50):48456-62
12374799
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4384-9
19240212
Kidney Blood Press Res. 2008;31(2):80-6
18319604
Am J Physiol Renal Physiol. 2002 Oct;283(4):F648-57
12217855
Biochem J. 2007 Oct 15;407(2):231-41
17617058
Science. 2001 Aug 10;293(5532):1107-12
11498583
Physiol Rev. 2006 Oct;86(4):1151-78
17015487
Kidney Int. 2008 Dec;74(11):1403-9
18800028
Nat Genet. 2006 Oct;38(10):1124-32
16964266
J Am Soc Nephrol. 2001 Jul;12(7):1335-1341
11423562
FEBS Lett. 2005 Feb 14;579(5):991-4
15710380
Am J Physiol Renal Physiol. 2001 Feb;280(2):F303-13
11208606
Nat Genet. 2003 Dec;35(4):372-6
14608358
Cell Metab. 2007 May;5(5):331-44
17488636
Am J Physiol Renal Physiol. 2006 Mar;290(3):F619-24
16204408
Am J Physiol Regul Integr Comp Physiol. 2005 Aug;289(2):R395-R401
16014448
J Cell Sci. 2008 Mar 1;121(Pt 5):675-84
18270262
J Am Soc Nephrol. 2005 Aug;16(8):2279-87
15958725
Kidney Int. 2006 Aug;70(4):630-4
16820787
J Clin Invest. 2005 May;115(5):1379-87
15841204
Structure. 2004 Jul;12(7):1303-11
15242606
Kidney Int. 2008 Mar;73(6):691-6
18094676
J Am Soc Nephrol. 2006 Sep;17(9):2402-13
16899520
Nat Clin Pract Nephrol. 2007 Nov;3(11):623-30
17957199
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4020-4
17360470
Annu Rev Physiol. 2008;70:329-55
17961084
Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10883-8
16832045
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4025-9
17360471