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, w e 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 bet a-galactosidase was performed in the heterozygous mutant mice to revea l the expression sites of AT-1a. The AT-1a receptor (that is, beta-gal actosidase) was expressed both in the afferent and efferent arteriolar smooth muscles and also in the mesangial cells. The effect of angiote nsin II on glomerular arterioles was directly observed using the hydro nephrotic 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 abolishe d by an AT-1 antagonist, CV-11974. In the homozygous null mutant mice, however, angiotensin II did not affect the arterioles at all. Electro n microscopic studies revealed that the mesangial cells made contact w ith the glomerular basement membrane (GBM) at the capillary neck and a lso 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 wide r. The mesangial matrix area appeared loose and enlarged, suggesting i mpaired mesangial matrix formation. In conclusion, via the AT-1a recep tor, angiotensin II equally constricts both the afferent and efferent arterioles and plays an essential role in maintaining the normal glome rular function and structure.