Wagner J, Klotz S, Haufe C C, Danser J A, Amann K, Ganten D, Ritz E
Department of Nephrology, University of Heidelberg, Germany.
J Hypertens. 1997 Apr;15(4):441-9. doi: 10.1097/00004872-199715040-00015.
To study the evolution of glomerulosclerosis after renal ablation in a model with abnormal regulation of the renin gene.
Four-month-old female ovariectomized hypertensive heterozygous transgenic rats (TGR) harbouring the murine REN-2 gene were compared with pressure-matched, pair-fed, stroke-prone, spontaneously hypertensive rats (SHRsp). Both groups were followed for 6 weeks after 70% subtotal nephrectomy (SNX) or sham operation.
Blood pressures in the SNX group at the end of the experiment were 193 +/- 3 mmHg in TGR and 199 +/- 5 mmHg in SHRsp. The final C(in) was 306 +/- 68 microliters/min per 100 g body weight in TGR that had undergone SNX and 550 +/- 93 microliters/min per 100 g body weight in SHR that had undergone SNX (P < 0.02), whereas inulin clearance (C(in)) in sham-operated pair-fed TGR and SHRsp controls did not differ from each other. The glomerulosclerosis index was 1.75 +/- 0.08 in perfusion-fixed TGR that had undergone SNX versus 1.21 +/- 0.03 in SHR that had undergone SNX (P < 0.005). In addition, the media thickness of preglomerular vessels was significantly greater in TGR that had undergone SNX (7.48 +/- 0.79 microns) than it was in SHRsp that had undergone SNX (5.27 +/- 1.38 microns, P < 0.02). Rat renal renin messenger RNA (mRNA) expression and, in parallel, mouse REN-2 gene expression were lower in TGR after SNX. Plasma renin and angiotensin II (ANG II) concentrations were reduced to a similar extent in both SNX groups, but plasma prorenin was higher in TGR that had undergone SNX than it was in SHRsp that had undergone SNX. The angiotensin II:I ratio in the kidney was significantly higher in TGR (P < 0.01). There was no significant difference between sham-operated or subtotally nephrectomized TGR and SHRsp with respect to angiotensin type 1 mRNA and angiotensinogen mRNA. The renal angiotensin converting enzyme activity, however, was significantly higher in sham operated and subtotally nephrectomized TGR than it was in sham operated SHRsp and in SHRsp that had undergone SNX.
Deterioration of renal function is accelerated in subtotally nephrectomized transgenic rats [TGR(mREN2)27] compared with that in comparably hypertensive SHRsp despite suppressed circulating active mRNA and decreased renal renin mRNA. Although alternative explanations are possible, this observation is consistent with a role for local ANG II in the genesis of glomerulosclerosis.
在肾素基因调控异常的模型中研究肾切除术后肾小球硬化的演变。
将携带小鼠REN - 2基因的4月龄雌性去卵巢高血压杂合转基因大鼠（TGR）与血压匹配、配对喂养、易中风的自发性高血压大鼠（SHRsp）进行比较。两组在70%次全肾切除术（SNX）或假手术后随访6周。
实验结束时，SNX组中TGR的血压为193±3 mmHg，SHRsp的血压为199±5 mmHg。接受SNX的TGR的最终菊粉清除率（C(in)）为每100 g体重306±68微升/分钟，接受SNX的SHR的C(in)为每100 g体重550±93微升/分钟（P<0.02），而假手术配对喂养的TGR和SHRsp对照组的菊粉清除率无差异。接受SNX的灌注固定TGR的肾小球硬化指数为1.75±0.08，接受SNX的SHR的肾小球硬化指数为1.21±0.03（P<0.005）。此外，接受SNX的TGR的球前血管中层厚度（7.48±0.79微米）显著大于接受SNX的SHRsp的球前血管中层厚度（5.27±1.38微米，P<0.02）。SNX后TGR的大鼠肾肾素信使核糖核酸（mRNA）表达以及与之平行的小鼠REN - 2基因表达降低。两个SNX组的血浆肾素和血管紧张素II（ANG II）浓度均降低到相似程度，但接受SNX的TGR的血浆前肾素高于接受SNX的SHRsp。TGR肾脏中的血管紧张素II: I比值显著更高（P<0.01）。假手术或次全肾切除的TGR和SHRsp在血管紧张素1型mRNA和血管紧张素原mRNA方面无显著差异。然而，假手术和次全肾切除的TGR的肾脏血管紧张素转换酶活性显著高于假手术的SHRsp和接受SNX的SHRsp。
与同等高血压的SHRsp相比，次全肾切除的转基因大鼠[TGR(mREN2)27]的肾功能恶化加速，尽管循环活性mRNA受到抑制且肾肾素mRNA减少。尽管可能有其他解释，但这一观察结果与局部ANG II在肾小球硬化发生中的作用一致。
