Document Detail

Novel signaling mechanisms of intracellular angiotensin II-induced NHE3 expression and activation in mouse proximal tubule cells.
MedLine Citation:
PMID:  23034941     Owner:  NLM     Status:  MEDLINE    
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.
X C Li; U Hopfer; J L Zhuo
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-03
Journal Detail:
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:
Created Date:  2012-12-17     Completed Date:  2013-04-02     Revised Date:  2013-12-18    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F1617-28     Citation Subset:  IM    
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MeSH Terms
Angiotensin II / metabolism*
Cell Line
Green Fluorescent Proteins / metabolism
Kidney Tubules, Proximal / cytology*,  metabolism*
MAP Kinase Signaling System / physiology
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
Reg. No./Substance:
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 Protein Kinase Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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