KEGG   PATHWAY: mmu04960
Entry
mmu04960                    Pathway                                

Name
Aldosterone-regulated sodium reabsorption - Mus musculus (mouse)
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
Pathway map
mmu04960  Aldosterone-regulated sodium reabsorption
mmu04960

Organism
Mus musculus (mouse) [GN:mmu]
Gene
15484  Hsd11b2; hydroxysteroid 11-beta dehydrogenase 2 [KO:K00071] [EC:1.1.1.-]
110784  Nr3c2; nuclear receptor subfamily 3, group C, member 2 [KO:K08555]
20276  Scnn1a; sodium channel, nonvoltage-gated 1 alpha [KO:K04824]
20277  Scnn1b; sodium channel, nonvoltage-gated 1 beta [KO:K04825]
20278  Scnn1g; sodium channel, nonvoltage-gated 1 gamma [KO:K04827]
20393  Sgk1; serum/glucocorticoid regulated kinase 1 [KO:K13302] [EC:2.7.11.1]
56379  Kcnj1; potassium inwardly-rectifying channel, subfamily J, member 1 [KO:K04995]
65962  Slc9a3r2; solute carrier family 9 (sodium/hydrogen exchanger), member 3 regulator 2 [KO:K13358]
83814  Nedd4l; neural precursor cell expressed, developmentally down-regulated gene 4-like [KO:K13305] [EC:2.3.2.26]
55948  Sfn; stratifin [KO:K06644]
16653  Kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
11928  Atp1a1; ATPase, Na+/K+ transporting, alpha 1 polypeptide [KO:K01539] [EC:7.2.2.13]
98660  Atp1a2; ATPase, Na+/K+ transporting, alpha 2 polypeptide [KO:K01539] [EC:7.2.2.13]
232975  Atp1a3; ATPase, Na+/K+ transporting, alpha 3 polypeptide [KO:K01539] [EC:7.2.2.13]
27222  Atp1a4; ATPase, Na+/K+ transporting, alpha 4 polypeptide [KO:K01539] [EC:7.2.2.13]
67821  Atp1b4; ATPase, (Na+)/K+ transporting, beta 4 polypeptide [KO:K01540]
11931  Atp1b1; ATPase, Na+/K+ transporting, beta 1 polypeptide [KO:K01540]
11932  Atp1b2; ATPase, Na+/K+ transporting, beta 2 polypeptide [KO:K01540]
11933  Atp1b3; ATPase, Na+/K+ transporting, beta 3 polypeptide [KO:K01540]
11936  Fxyd2; FXYD domain-containing ion transport regulator 2 [KO:K01538]
108017  Fxyd4; FXYD domain-containing ion transport regulator 4 [KO:K13359]
16334  Ins2; insulin II [KO:K04526]
16333  Ins1; insulin I [KO:K04526]
16000  Igf1; insulin-like growth factor 1 [KO:K05459]
16337  Insr; insulin receptor [KO:K04527] [EC:2.7.10.1]
16367  Irs1; insulin receptor substrate 1 [KO:K16172]
18709  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18708  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18710  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
18706  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
18707  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
74769  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
18607  Pdpk1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
18750  Prkca; protein kinase C, alpha [KO:K02677] [EC:2.7.11.13]
18751  Prkcb; protein kinase C, beta [KO:K19662] [EC:2.7.11.13]
18752  Prkcg; protein kinase C, gamma [KO:K19663] [EC:2.7.11.13]
26413  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
26417  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)
DOI:10.1152/ajprenal.2001.280.2.F303
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
Related
pathway
mmu00140  Steroid hormone biosynthesis
mmu04120  Ubiquitin mediated proteolysis
mmu04530  Tight junction
KO pathway
ko04960   

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