Epithelial Na+ channel (ENaC), hormones, and hypertension.
This minireview examines both the basic science and clinical observations over the past 20 years to show how and why overstimulation of the amiloride-sensitive epithelial Na(+) channel (ENaC) expressed by epithelial principal cells of the renal collecting duct may be responsible for a large portion of hypertension in modern society. This idea is based on the finding that, in Liddle syndrome, a mutation of the beta- and/or gamma-subunits of ENaC produces an activated ion channel, in turn resulting in severe hypertension that is resistant to most forms of conventional antihypertensive therapy. ENaC can also be stimulated to conduct sodium by two hormones: aldosterone and insulin. These hormones are both often elevated in obese individuals with therapy-resistant hypertension. Thus, overstimulation of ENaC by metabolic abnormalities in obese individuals may be a likely cause of the hypertension that accompanies obesity. The molecular mechanisms underlying both Liddle syndrome and obesity-related hypertension are different (i.e. genetic and hormonal, respectively), but both have the same end result, namely increased ENaC activity.
Bubien
James K
JK
Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294, USA. jbubien@bellsouth.net
D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D053503:Epithelial Sodium Channels / Q000737:chemistry*; D023281:Genomics; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism
D000959:Antihypertensive Agents; D053503:Epithelial Sodium Channels; D006728:Hormones; D007328:Insulin; D015221:Potassium Channels; D009569:Nitric Oxide; D000450:Aldosterone
Annu Rev Physiol. 2009;71:361-79
18928407
N Engl J Med. 1994 Jan 20;330(3):178-81
8264740
Am J Physiol Renal Physiol. 2009 Jan;296(1):F10-24
18508877
J Am Soc Nephrol. 1992 Oct;3(4 Suppl):S64-8
1457762
J Clin Invest. 1975 Apr;55(4):845-55
1120786
Am J Physiol Cell Physiol. 2001 Oct;281(4):C1118-30
11546647
Am J Physiol. 1998 May;274(5):C1373-9
9612225
J Am Soc Nephrol. 2008 Oct;19(10):1845-54
18753254
J Biol Chem. 2008 Mar 7;283(10):6033-9
18174164
Perm J. 2009 Winter;13(1):73-6
21373250
Am J Physiol Renal Physiol. 2003 Nov;285(5):F833-42
14532162
Hypertension. 1993 Sep;22(3):292-9
8349321
Hypertension. 2005 Sep;46(3):481-7
16116042
Hypertension. 1994 Jan;23(1 Suppl):I29-33
8282372
Mol Biol Cell. 2010 Mar 15;21(6):1047-58
20110346
J Am Soc Nephrol. 2005 Nov;16(11):3154-9
16192416
Lancet. 1987 Aug 22;2(8556):435-7
2887735
Am J Med Sci. 2001 Dec;322(6):302-7
11780687
Am J Physiol Cell Physiol. 2001 Nov;281(5):C1413-21
11600403
Ann Intern Med. 2009 Jun 2;150(11):776-83
19487712
J Am Soc Nephrol. 2008 Jan;19(1):125-34
18178802
J Biol Chem. 2007 Jul 13;282(28):20207-12
17502380
Biochem J. 2008 Oct 1;415(1):155-63
18498246
J Biol Chem. 1994 Jul 8;269(27):17780-3
8027031
Pflugers Arch. 2009 May;458(1):111-35
19277701
Hypertension. 2001 Nov;38(5):1124-9
11711509
Hypertension. 2008 Jun;51(6):1403-19
18391085
Traffic. 2007 Sep;8(9):1246-64
17605762
Nat Clin Pract Nephrol. 2006 Nov;2(11):624-30
17066054
Hypertension. 1989 Oct;14(4):367-74
2676858
Curr Opin Nephrol Hypertens. 2010 Jan;19(1):98-105
19996890
Am J Physiol Renal Physiol. 2008 Aug;295(2):F462-70
18524855
J Biol Chem. 2001 Mar 16;276(11):8557-66
11113130
Am J Physiol Renal Physiol. 2002 Aug;283(2):F221-35
12110505
Hypertension. 2004 Mar;43(3):518-24
14732721
Endocrinology. 2005 Dec;146(12):5079-85
16150899
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2805-8
16477034
Diabetologia. 1992 Jul;35(7):649-52
1644243
Circulation. 2007 Apr 17;115(15):1991-8
17404163
J Hypertens. 2001 Jan;19(1):107-12
11204289
Clin Chem. 2009 Dec;55(12):2093-6
19946064
Clin J Am Soc Nephrol. 2009 Dec;4(12):2045-50
19608710
Cell. 1994 Nov 4;79(3):407-14
7954808
Am J Physiol. 1996 Jan;270(1 Pt 1):C208-13
8772446
J Am Soc Nephrol. 2005 Nov;16(11):3167-74
16192418
Pharmacol Rep. 2009 Jan-Feb;61(1):105-15
19307698
J Clin Endocrinol Metab. 1997 Apr;82(4):1071-4
9100575
Curr Hypertens Rep. 2008 Dec;10(6):496-503
18959838
Hypertension. 2008 May;51(5):1252-8
18347227
Hosp Pract (Off Ed). 1994 Jul 15;29(7):95-8, 104-5
8027210
Physiol Rev. 2002 Jul;82(3):735-67
12087134
Yonsei Med J. 2000 Apr;41(2):276-80
10817031
Hypertension. 2010 Apr;55(4):813-8
20176994
Adv Exp Med Biol. 2004;559:359-68
18727255
Clin Nephrol. 2000 Jan;53(1):66-70
10661485
J Urol. 1986 Mar;135(3):557-8
3944906
Diabetologia. 1992 Mar;35(3):294-5
1563588
Hypertension. 2004 Jan;43(1):41-7
14638627