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Hypertension and alpha2-adrenergic receptor subtype expression

Objective

Objectives
The overall objective of this proposal is to investigate the role of alterations in expression and function of central and renal a2-AR subtypes in the development and/or maintenance of hypertension. This objective is informed by the established hypothesis that dysfunction of central catecholaminergic pathways and changes in renal a2-AR expression are involved in the development and/or sustaining of hypertension in humans, as well as in various animal models of genetic and acquired hypertension. This aim will be accomplished by studying the expression and functionality of the three a2 -AR subtypes in brain and kidney tissues and cells from appropriate animal models with or without treatment and comparing the findings to normotensive animals and by investigating the possible existence of variant alleles of the genes encodind a2-AR subtypes in a clinically hypertensive population and their correlation with different clinical characteristics of the patients

The overall objective of this proposal is to investigate the role of alterations in expression and function of central and renal a2-AR subtypes in the development and/or maintenance of hypertension. This objective is informed by the established hypothesis that dysfunction of central catecholaminergic pathways and changes in renal a2-AR expression are involved in the development and/or sustaining of hypertension in humans, as well as in various animal models of genetic and acquired hypertension and particularly in salt sensitive hypertension. This aim will be accomplished by studying the expression of the three a2-AR subtypes in brain and kidney tissues from appropriate animal models with or without treatment and comparing the findings to normotensive animals.

Specifically we will:
- Study the expression of different a2-AR gene transcripts in brain and kidney of normotensive rats over a period of 12 weeks by in situ hybridisation;
- Conduct studies on a2- AR expression in brain and kidney of three pathogenetically different rat models of hypertension: the genetically salt sensitive spontaneously hypertensive rat (SHR), the subtotally nephrectomized Wistar rat (with acquired saltdependent hypertention), and the two kidney, one-clip renovascular hypertensive rats during the renin-dependent phase and the non-renin dependent phase, which is postulated as being NaCl dependent and sympathetically mediated;
- Investigate whether lowering blood pressure in normotensive or spontaneously hypertensive rats modulates the expression or function of a2-AR subtypes;
- Determine whether hypertension develops and/or is controlled differently in mice with targeted inactivation(K.Omice) of individual receptor subtypes:
a. Changes in a2-AR subtype specific gene expression will be determined by RNase protection and In situ Hybridization;
b. Receptor functionality will be assessed by studying levels and function not only of the receptor protein, but also of the components of a2-AR signal transducing unit in membranes from tissues and cultured cells. This is important as recent molecular biological studies have shown, that changes of these components contextualise and condition a2 AR function.Kev words: Hypertension, a2 -AR subtypes, RNase protection, In situ Hybridization.01 01

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

University of Patras
Address
Patrasrion
26110 Patras
Greece

Participants (4)

DEUTSCHES PRIMATENZENTRUM GMBH
Germany
Address
4,Kellnerweg 4
37077 Goettingen
Institut National de la Santé et de la Recherche Médicale
France
Address
15,Rue De L'ecole De Médecine
75270 Paris
Institut National de la Santé et de la Recherche Médicale
France
Address
Chu Rangueil
31403 Toulouse
University of Turku
Finland
Address
10,Kiinamyllynkantu
20520 Turku