KEGG   PATHWAY: hsa04960
hsa04960                    Pathway                                
Aldosterone-regulated sodium reabsorption - Homo sapiens (human)
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.
Organismal Systems; Excretory system
Pathway map
hsa04960  Aldosterone-regulated sodium reabsorption

D00386  Triamterene (JP18/USP/INN)
D00443  Spironolactone (JP18/USP/INN)
D00649  Amiloride hydrochloride (USP)
D00986  Fludrocortisone acetate (JP18/USP)
D01115  Eplerenone (JP18/USAN/INN)
D01943  Canrenoate potassium (USAN)
D03363  Canrenone (USAN)
D03698  Desoxycorticosterone acetate (USP)
D03699  Desoxycorticosterone pivalate (USP)
D03792  Dicirenone (USAN)
D05020  Mexrenoate potassium (USAN)
D05640  Prorenoate potassium (USAN/INN)
D05912  Spiroxasone (USAN/INN)
D07447  Amiloride (INN)
D07792  Desoxycortone (INN)
D07967  Fludrocortisone (INN)
D10528  Aldosterone (INN)
D10633  Finerenone (JAN/USAN/INN)
D10892  Esaxerenone (JAN/INN)
D11667  Miricorilant (USAN/INN)
D12346  Idrevloride (USAN)
Homo sapiens (human) [GN:hsa]
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 subunit alpha [KO:K04824]
6338  SCNN1B; sodium channel epithelial 1 subunit beta [KO:K04825]
6340  SCNN1G; sodium channel epithelial 1 subunit gamma [KO:K04827]
6446  SGK1; serum/glucocorticoid regulated kinase 1 [KO:K13302] [EC:]
3758  KCNJ1; potassium inwardly rectifying channel subfamily J member 1 [KO:K04995]
9351  NHERF2; NHERF family PDZ scaffold protein 2 [KO:K13358]
23327  NEDD4L; NEDD4 like E3 ubiquitin protein ligase [KO:K13305] [EC:]
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:]
477  ATP1A2; ATPase Na+/K+ transporting subunit alpha 2 [KO:K01539] [EC:]
478  ATP1A3; ATPase Na+/K+ transporting subunit alpha 3 [KO:K01539] [EC:]
480  ATP1A4; ATPase Na+/K+ transporting subunit alpha 4 [KO:K01539] [EC:]
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:]
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]
110117499  P3R3URF-PIK3R3; P3R3URF-PIK3R3 readthrough [KO:K02649]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
5170  PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:]
5578  PRKCA; protein kinase C alpha [KO:K02677] [EC:]
5579  PRKCB; protein kinase C beta [KO:K19662] [EC:]
5582  PRKCG; protein kinase C gamma [KO:K19663] [EC:]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
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
Connell JM, Davies E
The new biology of aldosterone.
J Endocrinol 186:1-20 (2005)
Booth RE, Johnson JP, Stockand JD
Adv Physiol Educ 26:8-20 (2002)
Lee IH, Campbell CR, Cook DI, Dinudom A
Regulation of epithelial Na+ channels by aldosterone: role of Sgk1.
Clin Exp Pharmacol Physiol 35:235-41 (2008)
Viengchareun S, Le Menuet D, Martinerie L, Munier M, Pascual-Le Tallec L, Lombes M
The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology.
Nucl Recept Signal 5:e012 (2007)
Fuller PJ, Young MJ
Mechanisms of mineralocorticoid action.
Hypertension 46:1227-35 (2005)
Verrey F, Loffing J, Zecevic M, Heitzmann D, Staub O
SGK1: aldosterone-induced relay of Na+ transport regulation in distal kidney nephron cells.
Cell Physiol Biochem 13:21-8 (2003)
Pearce D, Kleyman TR
Salt, sodium channels, and SGK1.
J Clin Invest 117:592-5 (2007)
Grossmann C, Gekle M
New aspects of rapid aldosterone signaling.
Mol Cell Endocrinol 308:53-62 (2009)
Vallon V, Wulff P, Huang DY, Loffing J, Volkl H, Kuhl D, Lang F
Role of Sgk1 in salt and potassium homeostasis.
Am J Physiol Regul Integr Comp Physiol 288:R4-10 (2005)
Rogerson FM, Brennan FE, Fuller PJ
Dissecting mineralocorticoid receptor structure and function.
J Steroid Biochem Mol Biol 85:389-96 (2003)
Wang J, Barbry P, Maiyar AC, Rozansky DJ, Bhargava A, Leong M, Firestone GL, Pearce D
SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport.
Am J Physiol Renal Physiol 280:F303-13 (2001)
Good DW
Nongenomic actions of aldosterone on the renal tubule.
Hypertension 49:728-39 (2007)
hsa00140  Steroid hormone biosynthesis
hsa04120  Ubiquitin mediated proteolysis
hsa04530  Tight junction
KO pathway

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