Location and action of angiotensin II type 1 receptor in the renal microcirculation.
To localize angiotensin II type 1a (AT-1a) receptor and to reveal the physiological roles of angiotensin II in the renal microcirculation, we investigated the AT-1a gene deficient mice, generated by a targeted replacement of the AT-1a receptor loci by the lacZ gene (Sugaya et al, J Biol Chem 270: 18719, 1995). Immunohistochemical localization of beta-galactosidase was performed in the heterozygous mutant mice to reveal the expression sites of AT-1a. The AT-1a receptor (that is, beta-galactosidase) was expressed both in the afferent and efferent arteriolar smooth muscles and also in the mesangial cells. The effect of angiotensin II on glomerular arterioles was directly observed using the hydronephrotic mice. Angiotensin II similarly constricted both the afferent and efferent arterioles in the wild-type and heterozygous mutant mice in a dose-dependent manner. This constriction was completely abolished by an AT-1 antagonist, CV-11974. In the homozygous null mutant mice, however, angiotensin II did not affect the arterioles at all. Electron microscopic studies revealed that the mesangial cells made contact with the glomerular basement membrane (GBM) at the capillary neck and also with each other in the wild-type mice. However, in the homozygous null mutant mice, the mesangial cells lost the contact either with GBM or with each other and thus the capillary neck became remarkably wider. The mesangial matrix area appeared loose and enlarged, suggesting impaired mesangial matrix formation. In conclusion, via the AT-1a receptor, angiotensin II equally constricts both the afferent and efferent arterioles and plays an essential role in maintaining the normal glomerular function and structure.
Kimura
K
K
Second Department of Internal Medicine, University of Tokyo, Japan.
Inokuchi
S
S
Sugaya
T
T
Suzuki
N
N
Yoneda
H
H
Shirato
I
I
Mise
N
N
Oba
S
S
Miyashita
K
K
Tojo
A
A
Hirata
Y
Y
Goto
A
A
Sakai
T
T
Murakami
K
K
Omata
M
M
D000804:Angiotensin II / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006869:Hydronephrosis / Q000235:genetics / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008833:Microcirculation / Q000187:drug effects; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012079:Renal Circulation / Q000187:drug effects*; D001616:beta-Galactosidase / Q000378:metabolism
D011945:Receptors, Angiotensin; D000804:Angiotensin II; D001616:beta-Galactosidase