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The renal bumetanide-sensitive Na-K-2Cl cotransporter BSC-1/NKCC2 in essential hypertension and its regulation by norepinephrine

Sonalker, Prajakta Anilkumar (2006) The renal bumetanide-sensitive Na-K-2Cl cotransporter BSC-1/NKCC2 in essential hypertension and its regulation by norepinephrine. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The dissertation is based on the concept that pathogenesis of essential hypertension involves the kidney. In this regard, renal sodium ion transporters, responsible for sodium reabsorption and fluid balance, may be important candidates in hypertension. Many lines of evidence indicate that the sympathetic nervous system, via renal nerves, plays an important role in the pathogenesis of essential hypertension. The goals of the dissertation were to: 1) identify whether renal sodium ion transporter expression is altered in an animal model of essential hypertension, the Spontaneously Hypertensive Rat (SHR) and if so, its physiological significance; 2) determine the role of the sympathetic nervous system in regulation of renal sodium ion transporters and 3) elucidate the underlying molecular mechanism. Among the renal sodium transporters profiled in the SHR, the bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1) of the thick ascending limb was found to be most elevated; suggesting that increase in BSC-1 abundance may contribute to altered tubular function in SHR. In support of this conclusion, our results demonstrate that the natriuretic response to furosemide is greater in SHR versus its normotensive counterpart the Wistar-Kyoto Rat (WKY), resulting in normalization of blood pressure. Additionally, progression from pre-hypertensive to hypertensive state in SHR is accompanied by an increase in steady state protein levels of BSC-1 and its distribution to plasma membrane. Thus our biochemical and pharmacological data are consistent with the hypothesis that BSC-1 is involved in the pathogenesis of hypertension in SHR.Activation of renal sympathetic efferent nerves releases norepinephrine and, if chronic, increases arterial pressure. We hypothesize that long-term exposure of kidney to norepinephrine increases expression of renal sodium transport systems. Our results indicate that chronic 14-day norepinephrine infusion increased abundance of BSC-1 along with an increase in mean arterial blood pressure; an effect that could explain altered sodium handling associated with an over-active renal sympathetic system. Finally, studies in an immortalized thick ascending limb cell line show that regulation of BSC-1 by norepinephrine involves post-transcriptional control mechanisms via the â-adrenoceptor-cAMP-PKA pathway, and involves in part MAP kinases and that the á-adrenoceptor negatively regulates BSC-1. Further elucidation of the mechanism would suggest new strategies to treat diseases associated with an over-active sympathetic nervous system such as essential hypertension.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Sonalker, Prajakta Anilkumarpas68@pitt.eduPAS68
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRomero, Guillermo Gggr@pitt.eduGGR
Committee MemberAltschuler, Daniel Laltschul@server.pharm.pitt.edu
Committee MemberJackson, Edwin Kedj@pitt.eduEDJ
Committee MemberFriedman, Peter Apaf10@pitt.eduPAF10
Committee MemberHughey, Rebecca Phughey@dom.pitt.eduHUGHEYR
Date: 16 November 2006
Date Type: Completion
Defense Date: 19 October 2006
Approval Date: 16 November 2006
Submission Date: 16 November 2006
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: BSC-1/NKCC2; Essential hypertension; Norepinephrine; Renal sodium transport; Spontaneously Hypertensive Rat (SHR); Sympathetic nervous system
Other ID: http://etd.library.pitt.edu/ETD/available/etd-11162006-105643/, etd-11162006-105643
Date Deposited: 10 Nov 2011 20:05
Last Modified: 15 Nov 2016 13:51
URI: http://d-scholarship.pitt.edu/id/eprint/9687

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