Overexpression of angiotensinogen in proximal tubule leads to sodium-sensitivity of blood pressure

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Publication Type dissertation
School or College School of Medicine
Department Human Genetics
Author Ying, Jian
Title Overexpression of angiotensinogen in proximal tubule leads to sodium-sensitivity of blood pressure
Date 2010-04-19
Description Common genetic variation in angiotensinogen (AGT) predispose to essential hypertension EH in humans. Understanding the mechanism at play will require demonstration in experimental animals with phenotypic expression closely replicating the human condition. AGT is differentially regulated at various sites. Hence apportionment of systemic vs. intrarenal mechanisms to AGTmediated predisposition to EH is of fundamental relevance for drug targeting in the treatment of EH. Hypothesis. We propose that variation in AGT expression in the physiologic range, with normal feedback regulation of renin at play, leads, whether in humans or mouse, to moderate but chronic differences in plasma volume regulation and BP through the interplay of both systemic and renal mechanisms to an extent that varies with (1) gender, (2) genetic background, (3) dietary sodium and (4) duration of disease and aging. Research Aims. In an initial step to test this hypothesis, Dr. Lalouel and colleagues have already generated transgenic mice mouse (m) AGT in liver (L), the leading source of systemic AGT under normal diet. They have shown that constitutive mAGT overexpression affects both plasma AGT levels and BP, in the range seen in humans and in Smithies' 3-copy animals, in sodium-sensitive C57BL/6J (B6) but not in the sodium-resistant A/J backgrounds. Our specific aim was to complement these studies by generating and analyzing animals that overexpress homospecific mAGT in PT. This was achieved by placing the coding sequence of mouse AGT downstream from an internal ribosomal entry site (IRES) in the 3' UTR of the KAP gene by gene targeting. To set the stage for future research, we also developed an animal model that affords constitutive overexpression of homospecific mouse renin (mREN) in distal nephron. Results. We developed animals with overexpression of mAGT restricted to PT. We showed that the increased expression of mAGT was within physiological range. Having concluded this validation, we showed that restricted overexpression of mAGT in PT led to volume-sensitivity of BP. Manifestation of the genetic effect required both high sodium intake and expression in a sodiumsensitive background. We also developed animals that overexpress mREN in distal nephron.
Type Text
Publisher University of Utah
Subject Hypertension; Angiotensins; Mice
Subject MESH Hypertension; Angiotensins; Mice
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Overexpression of angiotensinogen in proximal tubule leads to sodium-sensitivity of blood pressure." Spencer S. Eccles Health Sciences Library. Print version of "Overexpressionn of angiotensinogen in proximal tubule leads to sodium-sensitivity of blood pressure." available at J. Willard Marriott Library Special Collection. QP6.6 2009.Y56.
Rights Management © Jian Ying
Format Medium application/pdf
Format Extent 1,343,312 bytes
Source Original: University of Utah Spencer S. Eccles Health Sciences Library
Conversion Specifications Original scanned on Fujitsi fi-5220G as 400 dpi to pdf using ABBYY FineReader 10
ARK ark:/87278/s6qc0j1w
Setname ir_etd
ID 192713
Reference URL https://collections.lib.utah.edu/ark:/87278/s6qc0j1w
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