| Effects of nominally selective inhibitors of the kinases PI3K, SGK1 and PKB on the insulin-dependent control of epithelial Na+ absorption. | |
| | |
MedLine Citation:
|
PMID: 20880397 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
BACKGROUND AND PURPOSE: Insulin-induced Na(+) retention in the distal nephron may contribute to the development of oedema/hypertension in patients with type 2 diabetes. This response to insulin is usually attributed to phosphatidylinositol-3-kinase (PI3K)/serum and glucocorticoid-inducible kinase 1 (SGK1) but a role for protein kinase B (PKB) has been proposed. The present study therefore aimed to clarify the way in which insulin can evoke Na(+) retention. EXPERIMENTAL APPROACH: We examined the effects of nominally selective inhibitors of PI3K (wortmannin, PI103, GDC-0941), SGK1 (GSK650394A) and PKB (Akti-1/2) on Na(+) transport in hormone-deprived and insulin-stimulated cortical collecting duct (mpkCCD) cells, while PI3K, SGK1 and PKB activities were assayed by monitoring the phosphorylation of endogenous proteins. KEY RESULTS: Wortmannin substantially inhibited basal Na(+) transport whereas PI103 and GDC-0941 had only very small effects. However, these PI3K inhibitors all abolished insulin-induced Na(+) absorption and inactivated PI3K, SGK1 and PKB fully. GSK650394A and Akti-1/2 also inhibited insulin-evoked Na(+) absorption and while GSK650394A inhibited SGK1 without affecting PKB, Akti-1/2 inactivated both kinases. CONCLUSION AND IMPLICATIONS: While studies undertaken using PI103 and GDC-0941 show that hormone-deprived cells can absorb Na(+) independently of PI3K, PI3K seems to be essential for insulin induced Na(+) transport. Akti-1/2 does not act as a selective inhibitor of PKB and data obtained using this compound must therefore be treated with caution. GSK650394A, on the other hand, selectively inhibits SGK1 and the finding that GSK650394A suppressed insulin-induced Na(+) absorption suggests that this response is dependent upon signalling via PI3K/SGK1. |
| | |
Authors:
|
Morag K Mansley; Stuart M Wilson |
Related Documents
:
|
11246877 - Insulin resistance with enhanced insulin signaling in high-salt diet-fed rats. 16375857 - Glucose activation of chrebp in hepatocytes occurs via a two-step mechanism. 1473267 - Effect of inhibitors and activators of tyrosine kinase on insulin imprinting in tetrahy... 6097227 - Carbamyl phosphate glucose transferase activity of glucose-6-phosphatase in the isolate... 15561957 - Development of late-stage diabetic nephropathy in ove26 diabetic mice. 12675667 - Impaired fasting glucose and impaired glucose tolerance in urban population in india. |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: British journal of pharmacology Volume: 161 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2010 Oct |
Date Detail:
|
Created Date: 2010-09-30 Completed Date: 2011-01-24 Revised Date: 2012-05-07 |
Medline Journal Info:
|
Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
|
Languages: eng Pagination: 571-88 Citation Subset: IM |
Affiliation:
|
Centre for Cardiovascular and Lung Biology, Division of Medical Sciences, College of Medicine, Dentistry and Nursing, University of Dundee, Dundee, UK. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Absorption Androstadienes / pharmacology Animals Benzoic Acids / pharmacology Benzylamines / pharmacology Bicyclo Compounds, Heterocyclic / pharmacology Cells, Cultured Epithelial Cells / drug effects*, metabolism, physiology Furans / pharmacology Immediate-Early Proteins / antagonists & inhibitors*, metabolism Indazoles / pharmacology Insulin / pharmacology Ion Transport / drug effects Kidney Tubules, Collecting / drug effects Membrane Potentials / drug effects, physiology Mice Phosphatidylinositol 3-Kinases / antagonists & inhibitors*, metabolism Protein-Serine-Threonine Kinases / antagonists & inhibitors*, metabolism Proto-Oncogene Proteins c-akt / antagonists & inhibitors*, metabolism Pyridines / pharmacology Pyrimidines / pharmacology Quinoxalines / pharmacology Sodium / metabolism* Sulfonamides / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
|
//Medical Research Council |
| Chemical | |
Reg. No./Substance:
|
0/2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; 0/Akt-I-1,2 compound; 0/Androstadienes; 0/Benzoic Acids; 0/Benzylamines; 0/Bicyclo Compounds, Heterocyclic; 0/Furans; 0/GSK 650394; 0/Immediate-Early Proteins; 0/Indazoles; 0/Insulin; 0/PI103; 0/Pyridines; 0/Pyrimidines; 0/Quinoxalines; 0/Sulfonamides; 19545-26-7/wortmannin; 7440-23-5/Sodium; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/serum-glucocorticoid regulated kinase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arach...
Next Document: The proton-coupled amino acid transporter, SLC36A1 (hPAT1), transports Gly-Gly, Gly-Sar and other Gl...