Kimura K, Inokuchi S, Sugaya T, Suzuki N, Yoneda H, Shirato I, Mise N, Oba S, Miyashita K, Tojo A, Hirata Y, Goto A, Sakai T, Murakami K, Omata M
Second Department of Internal Medicine, University of Tokyo, Japan.
Kidney Int Suppl. 1997 Dec;63:S201-4.
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.
为了定位血管紧张素II 1a型（AT-1a）受体并揭示血管紧张素II在肾微循环中的生理作用，我们研究了通过用lacZ基因靶向替换AT-1a受体基因座而产生的AT-1a基因缺陷小鼠（Sugaya等人，《生物化学杂志》270:18719，1995）。在杂合突变小鼠中进行β-半乳糖苷酶的免疫组织化学定位，以揭示AT-1a的表达位点。AT-1a受体（即β-半乳糖苷酶）在入球和出球小动脉平滑肌以及系膜细胞中均有表达。使用肾积水小鼠直接观察血管紧张素II对肾小球小动脉的作用。血管紧张素II以剂量依赖的方式同样收缩野生型和杂合突变小鼠的入球和出球小动脉。这种收缩被AT-1拮抗剂CV-11974完全消除。然而，在纯合无效突变小鼠中，血管紧张素II对小动脉根本没有影响。电子显微镜研究显示，在野生型小鼠中，系膜细胞在毛细血管颈部与肾小球基底膜（GBM）接触，并且彼此之间也有接触。然而，在纯合无效突变小鼠中，系膜细胞与GBM或彼此之间失去接触，因此毛细血管颈部明显变宽。系膜基质区域显得疏松且扩大，提示系膜基质形成受损。总之，血管紧张素II通过AT-1a受体同等地收缩入球和出球小动脉，并在维持正常肾小球功能和结构中起重要作用。
