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(Hypertension. 2004;43:445.)
© 2004 American Heart Association, Inc.

Scientific Contribution

Modifier Locus on Mouse Chromosome 3 for Renal Vascular Pathology in AT_1A Receptor-Deficiency

Thu H. Le; Agnes B. Fogo; Harmony R. Salzler; Tania Vinogradova; Michael I. Oliverio; Douglas A. Marchuk; Thomas M. Coffman

From Departments of Medicine and Genetics (T.H.L., H.R.S., T.V., M.I.O., D.A.M., T.M.C.), Duke University and Durham VA Medical Centers, Durham, NC and Department of Pathology (A.B.F.), Vanderbilt University Medical Center, Nashville Tenn.

Correspondence to Dr Thu Le, Assistant Professor, Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, 508 Fulton Street, Building 6, Room 1100, Durham, NC 27705. E-mail thu.le{at}duke.edu

We previously showed that the phenotype of mice with targeted disruption of the gene encoding the AT_1A receptor (Agtr1a), the major murine AT₁ receptor isoform, is strongly influenced by recessive genetic modifiers derived from the C57BL/6 or 129 inbred strains. To further evaluate the genetic modifiers on the C57BL/6 background, we performed backcrosses between F₁(C57BL/6x129) and C57BL/6 Agtr1a^-/- mice and analyzed the progeny, focusing on the development of structural lesions in the renal vasculature. In affected animals, these lesions are characterized by medial thickening of small arteries and arterioles in the kidney that are reminiscent of vascular lesions in patients with nephrosclerosis. Among 180 consecutive progeny, 170 (94%) survived to completion of the study. On masked pathological examination at age 8 months, 86 had intermediate to severe vascular lesions whereas 84 had no detectable lesions. Based on a hypothetical model of a single recessive modifier locus arising from the C57BL/6 background, the observed proportion of affected animals among the backcross progeny was not statistically different from that predicted by ² analysis (51% versus 50%; P=0.88). We next performed genomic microsatellite analysis in a subset of 121 backcross progeny using a panel of markers spanning 15 cM intervals across the mouse genome. By 2-point analysis, we found a region spanning 5 cM on chromosome 3, with significant linkage to the development of renal vascular lesions (LOD score: 3.3 to 3.8).

Key Words: receptors • angiotensin II, genetics • kidney • vessels • survival

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