| Novel signaling mechanisms of intracellular angiotensin II-induced NHE3 expression and activation in mouse proximal tubule cells. | |
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MedLine Citation:
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PMID: 23034941 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Expression of a cytosolic cyan fluorescent fusion protein of angiotensin II (ECFP/ANG II) in proximal tubules increases blood pressure in rodents. To determine cellular signaling pathways responsible for this response, we expressed ECFP/ANG II in transport-competent mouse proximal convoluted tubule cells (mPCT) from wild-type (WT) and type 1a ANG II receptor-deficient (AT(1a)-KO) mice and measured its effects on intracellular ANG II levels, surrogates of Na/H exchanger 3 (NHE3)-dependent Na(+) absorption, as well as MAP kinases and NF-κB signaling. In WT mPCT cells, ECFP/ANG II expression doubled ANG II levels, increased NHE3 expression and membrane phospho-NHE3 proteins threefold and intracellular Na(+) concentration by 65%. These responses were associated with threefold increases in phospho-ERK 1/2 and phospho-p38 MAPK, fivefold increases in p65 subunit of NF-κB, and threefold increases in phospho-IKKα/β (Ser 176/180) proteins. These signaling responses to ECFP/ANG II were inhibited by losartan (AT(1) blocker), PD123319 (AT(2) blocker), U0126 (MEK1/MEK2 inhibitor), and RO 106-9920 (NF-κB inhibitor). In mPCT cells of AT(1a)-KO mice, ECFP/ANG II also increased the levels of NHE3, p-ERK1/2, and p65 proteins above their controls, but considerably less so than in WT cells. In WT mice, selective expression of ECFP/ANG II in vivo in proximal tubules significantly increased blood pressure and indices of sodium reabsorption, in particular levels of phosphorylated NHE3 protein in the membrane fraction and proton gradient-stimulated (22)Na(+) uptake by proximal tubules. We conclude that intracellular ANG II may induce NHE3 expression and activation in mPCTs via AT(1a)- and AT(2) receptor-mediated activation of MAP kinases ERK 1/2 and NF-κB signaling pathways. |
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Authors:
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X C Li; U Hopfer; J L Zhuo |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural Date: 2012-10-03 |
Journal Detail:
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Title: American journal of physiology. Renal physiology Volume: 303 ISSN: 1522-1466 ISO Abbreviation: Am. J. Physiol. Renal Physiol. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-12-17 Completed Date: 2013-04-02 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 100901990 Medline TA: Am J Physiol Renal Physiol Country: United States |
Other Details:
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Languages: eng Pagination: F1617-28 Citation Subset: IM |
Affiliation:
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Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Angiotensin II
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metabolism* Animals Cell Line Green Fluorescent Proteins / metabolism Kidney Tubules, Proximal / cytology*, metabolism* MAP Kinase Signaling System / physiology Mice Mice, Knockout Mitogen-Activated Protein Kinase Kinases / metabolism NF-kappa B / metabolism Receptor, Angiotensin, Type 1 / deficiency, genetics, metabolism Receptor, Angiotensin, Type 2 / metabolism Signal Transduction / physiology* Sodium-Hydrogen Antiporter / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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2R01DK067299-07/DK/NIDDK NIH HHS; 2R56DK067299-06/DK/NIDDK NIH HHS; 5R01DK067299/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cyan Fluorescent Protein; 0/NF-kappa B; 0/Receptor, Angiotensin, Type 1; 0/Receptor, Angiotensin, Type 2; 0/Sodium-Hydrogen Antiporter; 0/sodium-hydrogen exchanger 3; 11128-99-7/Angiotensin II; 147336-22-9/Green Fluorescent Proteins; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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