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An investigation into the mechanism of action of aldosterone on ENaC: A search for endogenous substrates of SGK1.

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Call No.	QP606.P76 A44 2009
Author	Akerman, Bonnie L.
Title	An investigation into the mechanism of action of aldosterone on ENaC: A search for endogenous substrates of SGK1.
Date	2009
Abstract	It is well established that SGK1 plays a role in aldosterone mediated sodium transport. The intracellular localization of SGK1 has recently been demonstrated as mitochondrial. The studies described here evaluate the hypothesis that SGK1 phosphorylates a mitochondrial associated protein that, in turn, indirectly regulates ENaC. There were three aims of this thesis work: 1) determine the intracellular distribution of potential SGK1 substrates, 2) identify these potential substrates using Mass spectrometry analysis and 3) investigate the aldosterone/SGK1 influence on the identified substrates. It was demonstrated that SGK1 has both cytosolic and mitochondrial substrates. Mass spectrometry analysis of a mitochondrial preparation revealed several potential SGK1 substrates. NDRG1 was rediscovered as a renal SGK1 substrate. Aldosterone activation of the mineralocorticoid receptor caused a decrease in electrophoretic mobility of NDRG1 protein. The change in electrophoretic mobility was determined to be a result of a posttranslational modification and not a transcriptional event. Additionally, this change was determined to require PI3K/SGK1 and GSK3 activity. However, SGK1 phosphorylation of NDRG1 could not reproduce the aldosterone effect observed. This suggests that SGK1 phosphorylation of NDRG1 primes the protein for further modifications. Surprisingly, the aldosterone affect could not be mimicked by activation of the glucocorticoid receptor by dexamethasone. Within kidney cells, it was demonstrated that NDRG1 co-localizes to the mitochondria. Aldosterone treated cells exhibit a significant shift of NDRG1 intracellular localization from being predominantly mitochondrial to becoming cytosolic. Furthermore, the aldosterone induced modification of NDRG1 protein was found predominantly within the cytosolic fraction of the cell. This could be interpreted as SGK1 phosphorylation of NDRG1 results in NDRG1 disassociation from the mitochondria allowing it to then interact with another enzyme that results in further modification. The physiological consequence of such modifications is still unclear. However, it was demonstrated that extreme over-expression of NDRG1 within CCD cells results in a disturbance of paracellular resistance, presumably through an influence on tight junction formation. The second potential substrate investigated in these studies was Citrate synthase. The data presented here suggests that Citrate synthase is phosphorylated and can be phosphorylated by SGK1. Unfortunately, a correlation between phosphorylation status and the enzymatic activity of Citrate synthase was unable to be definitively established.
Description	xiv, 167 leaves : ill. (some col.) ; 28 cm.
Format	application/pdf
Advisor	Geza Fejes-Toth, D.M.D. Paul M. Guyre, Ph.D., R. Brooks Robey, M.D., Scott A. Gerber, Ph.D.
Subject	Subject Protein kinases. Aldosterone -- Physiological effect. Sodium -- Physiological transport. Sodium channels. Epithelial cells. Glucocorticoids. Medical Term Sgk protein.
College	Dartmouth Medical School -- Department of Physiology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.291

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	AN INVESTIGATION INTO THE MECHANISM OF ACTION OF ALDOSTERONE ON ENaC: A SEARCH FOR ENDOGENOUS SUBSTRATES OF SGK1. A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Physiology By Bonnie L. Akerman DARTMOUTH COLLEGE Hanover, New Hampshire September 21, 2009 Examining Committee: Géza Fejes-Tóth, D.M.D. Paul M. Guyre, Ph.D. R. Brooks Robey, M.D. Scott A. Gerber, Ph.D. Brain W. Pogue, Ph.D. Dean of Graduate Studies

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