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1 Department of Medicine, Duke University and Durham Veterans Affair Medical Centers, Durham, North Carolina 27705; 2 Department of Clinical Pharmacology and Therapeutics, University of Shizuoka, Shizuoka, Japan; 3 Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville, Florida 32610; and 4 Department of Pathology, University of North Carolina, Chapel Hill, North Carolina 27599
To examine the role of the type 1A
(AT1A) angiotensin receptor in
renal growth and development, we analyzed F2 progeny from a series of crosses between F1 mice that were heterozygous for a
targeted disruption of the AT1A
receptor gene
[Agtr1A-(+/
)]. Among 21-day-old weanling F2 mice, we found that 194 (32%) were homozygous for the wild-type allele
Agtr1A-(+/+), 299 (49%) were Agtr1A-(+/
), and 119 (19%)
were Agtr1A-(
/
). This
differed significantly from the proportions predicted by Mendelian
genetics (P = 0.01), suggesting that
the complete absence of AT1A
receptors is associated with a mild survival disadvantage.
Agtr1A-(
/
) mice grew
normally, and we found no significant differences in body weight or
heart and kidney weights in
Agtr1A-(+/+) and
Agtr1A-(
/
) mice examined at 21, 60, and 100 days. Protein and DNA content of kidneys and hearts
were also similar in weanling or adult
Agtr1A-(+/+) and Agtr1A-(
/
) mice. By
light microscopy with immunohistochemistry, kidneys from
Agtr1A-(
/
) were
essentially normal, with two exceptions: 1) there was marked hypertrophy of
the juxtaglomerular apparatus (JGA) and proximal expansion of
renin-producing cells along the afferent arterioles, and
2) some glomeruli showed evidence of mesangial expansion. We did not find the severe renal vascular lesions
or papillary atrophy that have been observed in angiotensinogen- or
angiotensin converting enzyme-deficient animals. We conclude that the
AT1A receptor is not essential for
the normal organogenesis of the kidney; however, its absence is
associated with mild mesangial expansion and JGA hypertrophy.
renin; gene targeting; kidney; mesangium; juxtaglomerular apparatus
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