KEGG   PATHWAY: hsa04960Help
Entry
hsa04960                    Pathway                                

Name
Aldosterone-regulated sodium reabsorption - Homo sapiens (human)
Description
Sodium transport across the tight epithelia of Na+ reabsorbing tissues such as the distal part of the kidney nephron and colon is the major factor determining total-body Na+ levels, and thus, long-term blood pressure. Aldosterone plays a major role in sodium and potassium metabolism by binding to epithelial mineralocorticoid receptors (MR) in the renal collecting duct cells localized in the distal nephron, promoting sodium resorption and potassium excretion. Aldosterone enters a target cell and binds MR, which translocates into the nucleus and regulates gene transcription. Activation of MR leads to increased expression of Sgk-1, which phosphorylates Nedd4-2, an ubiquitin-ligase which targets ENAC to proteosomal degradation. Phosphorylated Nedd4-2 dissociates from ENAC, increasing its apical membrane abundance. Activation of MR also leads to increased expression of Na+/K+-ATPase, thus causing a net increase in sodium uptake from the renal filtrate. The specificity of MR for aldosterone is provided by 11beta-HSD2 by the rapid conversion of cortisol to cortisone in renal cortical collecting duct cells. Recently, besides genomic effects mediated by activated MR, rapid aldosterone actions that are independent of translation and transcription have been documented.
Class
Organismal Systems; Excretory system
BRITE hierarchy
Pathway map
Aldosterone-regulated sodium reabsorption
hsa04960

All organismsOrtholog table
Disease
H00239  
Bartter syndrome
H00242  
Liddle syndrome
H00243  
Hyperkalemic distal renal tubular acidosis (RTA type 4)
H00603  
Hypertension exacerbated in pregnancy
H00719  
Leprechaunism
H00892  
Bronchiectasis with or without elevated sweat chloride
H00942  
Rabson-Mendenhall syndrome
H00998  
Alternating hemiplegia of childhood
H01228  
Insulin-resistant diabetes mellitus with acanthosis nigricans (IRAN)
H01603  
Primary aldosteronism
Drug
D00085  
Insulin (JAN/USP)
D00386  
Triamterene (JP17/USP/INN)
D00443  
Spironolactone (JP17/USP/INN)
D00649  
Amiloride hydrochloride (USP)
D01115  
Eplerenone (JP17/USAN/INN)
D01943  
Canrenoate potassium (USAN)
D03250  
Insulin glargine (USAN/INN)
D03363  
Canrenone (USAN)
D03698  
Desoxycorticosterone acetate (USP)
D03699  
Desoxycorticosterone pivalate (USP)
D04475  
Insulin aspart (USAN/INN)
D04477  
Insulin lispro (USP/INN)
D04540  
Insulin glulisine (USAN/INN)
D04541  
Insulin human, isophane (USP)
D04542  
Insulin human zinc (USP)
D04543  
Insulin human zinc, extended (USP)
D04544  
Insulin I 125 (USAN)
D04545  
Insulin I 131 (USAN)
D04546  
Insulin, dalanated (USAN)
D04547  
Insulin, isophane (USP)
D04548  
Insulin, neutral (USAN)
D04549  
Insulin zinc, extended (USP)
D04550  
Insulin zinc, prompt (USP)
D04551  
Insulin zinc (USP)
D05622  
Proinsulin human (USAN)
D05640  
Prorenoate potassium (USAN/INN)
D07447  
Amiloride (INN)
D07792  
Desoxycortone (INN)
D08080  
Insulin injection, biphasic isophane (BAN)
D09727  
Insulin degludec (USAN/INN)
D10528  
Aldosterone (INN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
3291  
HSD11B2; hydroxysteroid 11-beta dehydrogenase 2 [KO:K00071] [EC:1.1.1.-]
4306  
NR3C2; nuclear receptor subfamily 3 group C member 2 [KO:K08555]
6337  
SCNN1A; sodium channel epithelial 1 alpha subunit [KO:K04824]
6338  
SCNN1B; sodium channel epithelial 1 beta subunit [KO:K04825]
6340  
SCNN1G; sodium channel epithelial 1 gamma subunit [KO:K04827]
6446  
SGK1; serum/glucocorticoid regulated kinase 1 [KO:K13302] [EC:2.7.11.1]
3758  
KCNJ1; potassium voltage-gated channel subfamily J member 1 [KO:K04995]
9351  
SLC9A3R2; SLC9A3 regulator 2 [KO:K13358]
23327  
NEDD4L; neural precursor cell expressed, developmentally down-regulated 4-like, E3 ubiquitin protein ligase [KO:K13305] [EC:2.3.2.26]
2810  
SFN; stratifin [KO:K06644]
3845  
KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
476  
ATP1A1; ATPase Na+/K+ transporting subunit alpha 1 [KO:K01539] [EC:3.6.3.9]
477  
ATP1A2; ATPase Na+/K+ transporting subunit alpha 2 [KO:K01539] [EC:3.6.3.9]
478  
ATP1A3; ATPase Na+/K+ transporting subunit alpha 3 [KO:K01539] [EC:3.6.3.9]
480  
ATP1A4; ATPase Na+/K+ transporting subunit alpha 4 [KO:K01539] [EC:3.6.3.9]
23439  
ATP1B4; ATPase Na+/K+ transporting family member beta 4 [KO:K01540]
481  
ATP1B1; ATPase Na+/K+ transporting subunit beta 1 [KO:K01540]
482  
ATP1B2; ATPase Na+/K+ transporting subunit beta 2 [KO:K01540]
483  
ATP1B3; ATPase Na+/K+ transporting subunit beta 3 [KO:K01540]
486  
FXYD2; FXYD domain containing ion transport regulator 2 [KO:K01538]
53828  
FXYD4; FXYD domain containing ion transport regulator 4 [KO:K13359]
3630  
INS; insulin [KO:K04526]
3479  
IGF1; insulin like growth factor 1 [KO:K05459]
3643  
INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
3667  
IRS1; insulin receptor substrate 1 [KO:K16172]
5295  
PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  
PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  
PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
5290  
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  
PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5170  
PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
5578  
PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
5579  
PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
5582  
PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
5594  
MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  
MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
Compound
C00238  
Potassium cation
C00575  
3',5'-Cyclic AMP
C00698  
Cl-
C00735  
Cortisol
C00762  
Cortisone
C01330  
Sodium cation
C01780  
Aldosterone
C05981  
Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Connell JM, Davies E
  Title
The new biology of aldosterone.
  Journal
J Endocrinol 186:1-20 (2005)
DOI:10.1677/joe.1.06017
Reference
  Authors
Booth RE, Johnson JP, Stockand JD
  Title
Aldosterone.
  Journal
Adv Physiol Educ 26:8-20 (2002)
DOI:10.1152/advan.00123.2015
Reference
  Authors
Lee IH, Campbell CR, Cook DI, Dinudom A
  Title
Regulation of epithelial Na+ channels by aldosterone: role of Sgk1.
  Journal
Clin Exp Pharmacol Physiol 35:235-41 (2008)
DOI:10.1111/j.1440-1681.2007.04844.x
Reference
  Authors
Viengchareun S, Le Menuet D, Martinerie L, Munier M, Pascual-Le Tallec L, Lombes M
  Title
The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology.
  Journal
Nucl Recept Signal 5:e012 (2007)
DOI:10.1621/nrs.05012
Reference
  Authors
Fuller PJ, Young MJ
  Title
Mechanisms of mineralocorticoid action.
  Journal
Hypertension 46:1227-35 (2005)
DOI:10.1161/01.HYP.0000193502.77417.17
Reference
  Authors
Verrey F, Loffing J, Zecevic M, Heitzmann D, Staub O
  Title
SGK1: aldosterone-induced relay of Na+ transport regulation in distal kidney nephron cells.
  Journal
Cell Physiol Biochem 13:21-8 (2003)
DOI:10.1159/000070246
Reference
  Authors
Pearce D, Kleyman TR
  Title
Salt, sodium channels, and SGK1.
  Journal
J Clin Invest 117:592-5 (2007)
DOI:10.1172/JCI31538
Reference
  Authors
Grossmann C, Gekle M
  Title
New aspects of rapid aldosterone signaling.
  Journal
Mol Cell Endocrinol 308:53-62 (2009)
DOI:10.1016/j.mce.2009.02.005
Reference
  Authors
Vallon V, Wulff P, Huang DY, Loffing J, Volkl H, Kuhl D, Lang F
  Title
Role of Sgk1 in salt and potassium homeostasis.
  Journal
Am J Physiol Regul Integr Comp Physiol 288:R4-10 (2005)
DOI:10.1152/ajpregu.00369.2004
Reference
  Authors
Rogerson FM, Brennan FE, Fuller PJ
  Title
Dissecting mineralocorticoid receptor structure and function.
  Journal
J Steroid Biochem Mol Biol 85:389-96 (2003)
DOI:10.1016/S0960-0760(03)00200-0
Reference
  Authors
Wang J, Barbry P, Maiyar AC, Rozansky DJ, Bhargava A, Leong M, Firestone GL, Pearce D
  Title
SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport.
  Journal
Am J Physiol Renal Physiol 280:F303-13 (2001)
Reference
  Authors
Good DW
  Title
Nongenomic actions of aldosterone on the renal tubule.
  Journal
Hypertension 49:728-39 (2007)
DOI:10.1161/01.HYP.0000259797.48382.b2
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