Aldosterone regulation of intestinal Na absorption involves SGK-mediated changes in NHE3 and Na+ pump activity.
Aldosterone-induced intestinal Na(+) absorption is mediated by increased activities of apical membrane Na(+)/H(+) exchange (aNHE3) and basolateral membrane Na(+)-K(+)-ATPase (BLM-Na(+)-K(+)-ATPase) activities. Because the processes coordinating these events were not well understood, we investigated human intestinal Caco-2BBE cells where aldosterone increases within 2-4 h of aNHE3 and alpha-subunit of BLM-Na(+)-K(+)-ATPase, but not total abundance of these proteins. Although aldosterone activated Akt2 and serum glucorticoid kinase-1 (SGK-1), the latter through stimulation of phosphatidylinositol 3-kinase (PI3K), only the SGK-1 pathway mediated its effects on Na(+)-K(+)-ATPase. Ouabain inhibition of the early increase in aldosterone-induced Na(+)-K(+)-ATPase activation blocked most of the apical NHE3 insertion, possibly by inhibiting Na(+)-K(+)-ATPase-induced changes in intracellular sodium concentration ([Na](i)). Over the next 6-48 h, further increases in aNHE3 and BLM-Na(+)-K(+)-ATPase activity and total protein expression were observed to be largely mediated by aldosterone-activated SGK-1 pathway. Aldosterone-induced increases in NHE3 mRNA, for instance, could be inhibited by RNA silencing of SGK-1, but not Akt2. Additionally, aldosterone-induced increases in NHE3 promoter activity were blocked by silencing SGK-1 as well as pharmacological inhibition of PI3K. In conclusion, aldosterone-stimulated intestinal Na(+) absorption involves two phases. The first phase involves stimulation of PI3K, which increases SGK-dependent insertion and function of BLM-Na(+)-K(+)-ATPase and subsequent increased membrane insertion of aNHE3. The latter may be caused by Na(+)-K(+)-ATPase-induced changes in [Na] or transcellular Na flux. The second phase involves SGK-dependent increases in total NHE3 and Na(+)-K(+)-ATPase protein expression and activities. The coordination of apical and BLM transporters after aldosterone stimulation is therefore a complex process that requires multiple time- and interdependent cellular processes.
Musch
Mark W
MW
Univ. of Chicago, Chicago, IL 60637, USA.
Lucioni
Alvaro
A
Chang
Eugene B
EB
D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000502:physiology; D018938:Caco-2 Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012964:Sodium / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
D000450:Aldosterone; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012964:Sodium; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000254:Sodium-Potassium-Exchanging ATPase; D000099184:Serum-Glucocorticoid Regulated Kinases; C000613385:SLC9A3 protein, human
Mol Endocrinol. 2001 Apr;15(4):575-88
11266509
Am J Physiol. 1999 May;276(5):C1205-17
10329970
Am J Physiol. 1993 Oct;265(4 Pt 1):G775-82
8238361
Steroids. 2002 May;67(6):483-91
11960625
Am J Physiol. 1996 Jan;270(1 Pt 1):G29-41
8772498
Mol Biol Cell. 2006 Jan;17(1):317-26
16267270
Am J Physiol Cell Physiol. 2006 Feb;290(2):C492-8
16192298
Am J Physiol. 1996 Sep;271(3 Pt 2):F629-36
8853425
Am J Physiol Cell Physiol. 2006 Dec;291(6):C1247-57
16807298
Gastroenterology. 2001 May;120(6):1393-403
11313309
Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3010-5
9096337
Am J Physiol. 1998 Mar;274(3):C586-94
9530089
FEBS Lett. 1983 Mar 7;153(1):141-5
6298004
Am J Physiol Gastrointest Liver Physiol. 2002 Oct;283(4):G975-85
12223358
Am J Physiol Gastrointest Liver Physiol. 2001 Feb;280(2):G222-8
11208544
Anal Biochem. 2000 Oct 15;285(2):194-204
11017702
Eur J Morphol. 1998 Aug;36 Suppl:67-73
9825896
J Biol Chem. 1997 Nov 7;272(45):28672-9
9353335
J Biol Chem. 2003 May 9;278(19):16494-501
12595524
Am J Physiol. 1994 Sep;267(3 Pt 1):C796-803
7943208
J Physiol. 2001 Dec 1;537(Pt 2):537-52
11731584
Ann N Y Acad Sci. 1981;372:626-36
6280558
J Biol Chem. 1989 Nov 5;264(31):18638-44
2553716
Am J Physiol Cell Physiol. 2007 Nov;293(5):C1489-97
17728397
Am J Physiol. 1998 Sep;275(3):C693-701
9730953
Ann N Y Acad Sci. 2003 Apr;986:554-61
12763889
FASEB J. 2003 Oct;17(13):1966-8
12923071
J Membr Biol. 2001 Dec 1;184(3):255-61
11891550
Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1549-58
17307723
J Biol Chem. 2002 Jun 28;277(26):23714-24
11948184
Pflugers Arch. 1993 Mar;422(6):546-51
8385769
J Clin Invest. 2003 Apr;111(7):931-43
12671039
Pflugers Arch. 2004 Apr;448(1):29-35
14716489
J Physiol. 1969 Jun;202(2):305-27
4306542
Am J Physiol Renal Physiol. 2007 Apr;292(4):F1219-28
17190911
Am J Physiol Cell Physiol. 2007 Jan;292(1):C396-404
16971495
Am J Physiol Renal Physiol. 2007 Nov;293(5):F1518-32
17670901
J Biol Chem. 1993 Jan 5;268(1):206-11
8380155
Pflugers Arch. 2001 Mar;441(6):781-6
11316261
Surgery. 1994 Aug;116(2):388-94; discussion 394-5
8048004
J Clin Invest. 1994 Jan;93(1):106-13
8282777
Contrib Nephrol. 1998;123:205-19
9761970
Poult Sci. 2003 Jul;82(7):1127-33
12872969
J Biol Chem. 1999 Feb 12;274(7):3978-87
9933588
J Biol Chem. 2002 May 24;277(21):18694-702
11907028
Am J Physiol Cell Physiol. 2006 Mar;290(3):C757-63
16251474
Surgery. 1994 Aug;116(2):401-7; discussion 408
8048006
J Biol Chem. 1998 Apr 10;273(15):8790-8
9535857
Am J Physiol Cell Physiol. 2003 Nov;285(5):C1122-30
12839832
Am J Physiol Cell Physiol. 2005 Oct;289(4):C802-10
15888551
J Cell Sci. 1993 Jun;105 ( Pt 2):445-60
8408276
J Exp Zool. 1997 Dec 1;279(5):476-83
9392869
Am J Physiol Cell Physiol. 2003 Nov;285(5):C1246-54
12878493
Cell Mol Biol (Noisy-le-grand). 1999 Sep;45(6):805-13
10541477
Am J Physiol Renal Physiol. 2004 Jun;286(6):F1232-8
15039143
Am J Physiol. 1998 May;274(5):C1261-72
9612213
J Biol Chem. 1998 Nov 6;273(45):29972-8
9792717
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6556-61
10823893
Adv Physiol Educ. 2002 Dec;26(1-4):8-20
11850323