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REGULATION OF RENAL PROXIMAL TUBULE SODIUM TRANSPORTERS
DURING HIGH BLOOD PRESSURE
by
Anne D.M. Riquier
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements of the Degree
DOCTOR OF PHILOSOPHY
(SYSTEMS BIOLOGY AND DISEASE)
December 2009
Copyright 2009 Anne D.M. Riquier
Object Description
| Title | Regulation of renal proximal tubule sodium transporters during high blood pressure |
| Author | Riquier, Anne D. M. |
| Author email | ariquier@gmail.com; riquier@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Systems Biology & Disease |
| School | Keck School of Medicine |
| Date defended/completed | 2009-10-23 |
| Date submitted | 2009 |
| Restricted until | Unrestricted |
| Date published | 2009-10-27 |
| Advisor (committee chair) | McDonough, Alicia |
| Advisor (committee member) |
Garner, Judy Okamoto, Curtis Yu, Alan Peti-Peterdi, Janos |
| Abstract | Na+ and volume homeostasis is controlled by the kidneys and key to blood pressure (BP) regulation. The kidneys respond to an increase in BP by decreasing Na+/H2O reabsorption (pressure natriuresis, diuresis) to decrease ECFV and BP. Conversely, a decrease in BP triggers Na+/H2O retaining mechanisms. Sodium transport can be regulated by altering transporter pool size, activity, and/or trafficking. In the proximal tubule (PT), trafficking is essential for the NHE3 and NaPi2 regulation. When BP increases, both retract away from the microvilli, NHE3 to the base, NaPi2 to endosomes. The aims of this dissertation were to determine: 1) the molecular basis of the differential trafficking patterns of NHE3 and NaPi2 during acute hypertension; 2) the role of acute AngII in the trafficking of PT sodium transporters; 3) the role of phosphorylation in the NHE3 and distal tubule NCC regulation during hypertension. Results: NHE3 and NaPi2 are segregated into domains: NHE3 to lipid rafts and NaPi2 to non-rafts. These domain properties may play a role in their distinct trafficking patterns: NHE3 remains in rafts and settles to the base of the microvilli while NaPi2 is endocytosed. We then investigated the signaling mechanisms responsible for the trafficking of Na+ transporters. After acute angiotensin converting enzyme inhibition, NHE3 is at the base of the microvilli and NaPi2 in subapical cytoplasmic vesicles; after 20 min AngII, NHE3, NaPi2 and associated proteins redistributed into the microvilli. Trafficking likely contributes to the rapid increase in PT Na+/H2O reabsorption. Finally, we showed that during acute and chronic hypertension, there was no difference in NHE3pSer552 or NCCpThr60/total ratio. Compared to sham infused mice (1.00), AngII decreased NHE3 to 0.70 plus or minus 0.09, with no change in phosphorylation, increased NCC to 2.20 plus or minus 0.29 and NCC-P/total ratio to 2.16 plus or minus 0.45.; In the PTAT1RKO, AngII infusion increased BP 20mmHg less than in WT, decreased NHE3 to 0.55 plus or minus 0.07 (no change in phosphorylation), and increased NCC to 1.66 plus or minus 0.19 (no change in phosphorylation). We conclude that in WT, increased NCC contributes to AngII-induced hypertension while decreased NHE3 compensates for hypertension. Removal of PTAT1R facilitates pressure natriuresis by further decreasing PT transporters and blunting NCC increase during AngII infusion. |
| Keyword | hypertension; sodium transport; kidney |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m2693 |
| Rights | Riquier, Anne D. M. |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Riquier-3230 |
| Archival file | uscthesesreloadpub_Volume32/etd-Riquier-3230.pdf |
Description
| Title | Page 1 |
| Full text | REGULATION OF RENAL PROXIMAL TUBULE SODIUM TRANSPORTERS DURING HIGH BLOOD PRESSURE by Anne D.M. Riquier A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements of the Degree DOCTOR OF PHILOSOPHY (SYSTEMS BIOLOGY AND DISEASE) December 2009 Copyright 2009 Anne D.M. Riquier |
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