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
hsa04960  Aldosterone-regulated sodium reabsorption
hsa04960

Ortholog 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)
D00986  Fludrocortisone acetate (JP17/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)
D07967  Fludrocortisone (INN)
D08080  Insulin injection, biphasic isophane (BAN)
D09727  Insulin degludec (USAN/INN)
D10528  Aldosterone (INN)
D10633  Finerenone (JAN/USAN/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
KO pathway
ko04960   
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