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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-11162006-105643 |
| Date | 16 November 2006 |
| Creators | Sonalker, Prajakta Anilkumar |
| Contributors | Daniel L. Altschuler, Ph.D., Guillermo G. Romero, Ph.D., Rebecca P. Hughey, Ph.D., Edwin K. Jackson, Ph.D., Peter A. Friedman, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-11162006-105643/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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