Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Jun 5;284(23):15564-72.
doi: 10.1074/jbc.M806584200. Epub 2009 Mar 23.

Angiotensin-converting Enzyme Is a Modifier of Hypertensive End Organ Damage

Affiliations
Free PMC article

Angiotensin-converting Enzyme Is a Modifier of Hypertensive End Organ Damage

Xiaojun Liu et al. J Biol Chem. .
Free PMC article

Abstract

Severe forms of hypertension are characterized by high blood pressure combined with end organ damage. Through the development and refinement of a transgenic rat model of malignant hypertension incorporating the mouse renin gene, we previously identified a quantitative trait locus on chromosome 10, which affects malignant hypertension severity and morbidity. We next generated an inducible malignant hypertensive model where the timing, severity, and duration of hypertension was placed under the control of the researcher, allowing development of and recovery from end organ damage to be investigated. We have now generated novel consomic Lewis and Fischer rat strains with inducible hypertension and additional strains that are reciprocally congenic for the refined chromosome 10 quantitative trait locus. We have captured a modifier of end organ damage within the congenic region and, using a range of bioinformatic, biochemical and molecular biological techniques, have identified angiotensin-converting enzyme as the modifier of hypertension-induced tissue microvascular injury. Reciprocal differences between angiotensin-converting enzyme and the anti-inflammatory tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro in the kidney, a tissue susceptible to end organ damage, suggest a mechanism for the amelioration of hypertension-dependent damage.

Figures

FIGURE 1.
FIGURE 1.
Production of the congenic strains and mapping of the MOD QTL. a, Ren2.F males and Lewis females were bred to produce F1 animals. F1 males were backcrossed to Lewis or F344 females, respectively, for 12 generations, the choice of male at each generation being marker-assisted. Brother-sister matings produced Ren2F-MOD-L and Ren2L-MOD-F strains. b, the extent of the congenic region on chromosome 10 (hatched box) was determined using informative microsatellites and further refined (black box) by scanning informative single nucleotide polymorphisms with high resolution melting analysis.
FIGURE 2.
FIGURE 2.
Transgene expression in consomic and congenic lines before and after induction, and telemetric analysis of mean arterial blood pressure (n = 6/group/experiment). a, plasma active renin. b, mouse Ren2 expression in the liver, relative to wsbcr1 expression. c, central panel shows the daily mean arterial blood pressures for 5 days prior to induction and for the 10-day duration of induction. Left panel, variation in MABP between strains prior to induction. Right panel, change in MABP during induction. **, p < 0.01 versus parental consomic. Ren2.L is shown as a dotted line, and the other groups are marked as per the key.
FIGURE 3.
FIGURE 3.
Pathological assessment of strains after induction in mesentery (a), pancreas (b), and kidney (c) is shown. The severity of microvascular injury was estimated with a 5-point ordered categorical scale according to the presence of reactive myoadventitial changes only (scoring 1 or 2 if widespread and severe) or additional destructive lesions, characterized by intramural necrosis and/or fibrinoid change (scoring 3–5 for a single focus, 2–3 foci, or >3 foci/section, respectively). In the heart (d), severity was the mean count of necroinflammatory lesions (NI) in interventricular septum, left and right ventricle per cardiac transverse section. e, mesentery: small artery showing reactive myoadventitial changes: plump reactive medial myocytes and disarray, merging with adventitial proliferation and mononuclear inflammatory cell infiltration (approximate magnification, ×40). f, kidney: small artery showing a destructive lesion. There is mild adventitial proliferation and mononuclear cell infiltration surrounding a media with coagulative necrosis, intramural hemorrhage, and luminal endothelial hypertrophy (×60). g, heart, showing a necroinflammatory lesion affecting a right ventricular papillary muscle, with central coagulative necrosis, a surrounding mononuclear cell infiltrate and myofibroblastic proliferation (×20).
FIGURE 4.
FIGURE 4.
Renal hemodynamics were assessed before and following 7-day induction, by measuring renal clearance of para-amino hippuric acid and fluorescein isothiocyanate-inulin (n = 6/group/experiment) noninduced RPF (a), ΔRPF after 7 days induction (b), noninduced GFR (c), and ΔGFR after 7 days induction (d). *, p < 0.05; **, p < 0.01 versus parental consomic. Dark gray, Ren2.F; black, Ren2F-MOD-L; light gray, Ren2.L-MOD-F; white, Ren2.L).
FIGURE 5.
FIGURE 5.
a, candidate genes, lying within or just outside the congenic region defined in Ren2.F-MOD-L. b, Ace mRNA expression in consomic and congenic strains (expressed as arbitrary units relative to 18 S) in noninduced kidney (panel i) and following 7 (panel ii) or 10 days induction (panel iii). *, p < 0.05; **, p < 0.01; ***, p < 0.001 versus parental consomic (n = 6).
FIGURE 6.
FIGURE 6.
a, serum Ace activity in noninduced animals (panel i) or following 7 (panel ii) or 10 days induction (panel iii). *, p < 0. 05; **, p < 0.01; ***, p < 0.001 (n = 6). b, panel i, Western analysis shows the relative expression of ACE in kidney between Fischer (tracks 1–6) and Lewis (tracks 7–12) rats. The upper panel shows immunoblot using ACE antibody, and the lower panel shows glyceraldehyde-3-phosphate dehydrogenase loading control. Panel ii, protein quantification by densitometry. The ratio of the means ± S.E. is shown (***, p < 0.001). c, the dose-response pressor effect of angiotensin I in cohorts of noninduced Ren2.F (gray line; n = 5) and Ren2.L (dotted line; n = 5) rats. The values are the means ± S.E. *, p < 0.05; **, p < 0.01.

Similar articles

See all similar articles

Cited by 10 articles

See all "Cited by" articles

References

    1. Lip G. Y., Beevers M., Beevers D. G. ( 1995) J. Hypertens. 13, 915– 924 - PubMed
    1. Lip G. Y., Beevers M., Beevers G. ( 1994) J. Hypertens. 12, 1297– 1305 - PubMed
    1. Edmunds E., Beevers D. G., Lip G. Y. ( 2000) J. Hum. Hypertens. 14, 159– 161 - PubMed
    1. Kincaid-Smith P. ( 1981) Aust. N. Z. J. Med. 11, 64– 68 - PubMed
    1. Collidge T. A., Lammie G. A., Fleming S., Mullins J. J. ( 2004) Prog. Biophys. Mol. Biol. 84, 301– 319 - PubMed

Publication types

MeSH terms

Feedback