内源性不对称二甲基精氨酸与大鼠嘌呤霉素肾病相关的高血压

Endogenous asymmetrical dimethylarginine and hypertension associated with puromycin nephrosis in the rat.

作者信息

Sato J, Masuda H, Tamaoki S, Hamasaki H, Ishizaka K, Matsubara O, Azuma H

机构信息

Department of Medicinal Chemistry, Institute for Medical and Dental Engineering, Faculty of Medicine, Tokyo Medical and Dental University, Japan.

出版信息

Br J Pharmacol. 1998 Oct;125(3):469-76. doi: 10.1038/sj.bjp.0702101.

DOI:10.1038/sj.bjp.0702101

PMID:9806329

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1565650/

Abstract

The present experiments were designed to investigate the role of asymmetrical NG,NG-dimethyl-L-arginine (ADMA) in causing hypertension associated with the focal and segmental glomerulosclerosis (FSGS) produced by a single bolus of puromycin aminonucleoside (PAN) and successive injection of protamine for 7 days in rats which had undergone unilateral nephrectomy. 2. After the unilateral nephrectomy, and administering PAN and protamine, histological examinations of the kidney revealed a typical FSGS, that is, evident abnormalities including segmental mesangial proliferation, obliteration of glomerular capillary lumens and adhesions between the glomerulus and Bowman's capsule could be observed. Changes in the glomerular epithelial cells consisted of the swelling with bleb formation. 3. In the FSGS rats, urine volume and urinary protein were significantly (P<0.05 and P<0.005) increased throughout 4-week experimental period, while the creatinine clearance was significantly (P<0.005) and transiently decreased, and recovered 4 weeks later. These changes were associated with the sustained elevation of the systolic blood pressure. 4. ADMA levels in aortic endothelial cells, plasma and urine were significantly (P<0.05 and P<0.005) increased in the FSGS rats, but the level in the kidney remained unchanged. 5. The basal level and net production of cyclic GMP in the aortic vessel wall with endothelium when stimulated by norepinephrine and acetylcholine were significantly (P<0.05 and P<0.01) attenuated in the FSGS rats. 6. There were significant and positive correlations between systolic blood pressure (y) and ADMA levels (x) in endothelial cells (y=4.43x+122.2, r=0.979, P<0.0001), plasma (y=0.10x+71.9, r=0.921, P<0.001) and urine (y=0.48x+126.9, r =0.699, P<0.005), but not significant in the kidney (y=0.06x+102.7, r=0.252, NS). 7. These findings suggest that ADMA as an endogenous inhibitor of NO synthesis may play an important role for the pathogenesis in the hypertension associated with the experimental FSGS in the rat.

摘要

本实验旨在研究不对称NG，NG-二甲基-L-精氨酸（ADMA）在单侧肾切除大鼠中，由单次注射嘌呤霉素氨基核苷（PAN）和连续7天注射鱼精蛋白所导致的局灶节段性肾小球硬化（FSGS）相关高血压形成过程中的作用。2. 单侧肾切除并给予PAN和鱼精蛋白后，肾脏组织学检查显示典型的FSGS，即可以观察到明显异常，包括节段性系膜增生、肾小球毛细血管腔闭塞以及肾小球与鲍曼囊之间的粘连。肾小球上皮细胞的变化包括肿胀并形成小泡。3. 在FSGS大鼠中，整个4周实验期内尿量和尿蛋白显著增加（P<0.05和P<0.005），而肌酐清除率显著（P<0.005）且短暂降低，并在4周后恢复。这些变化与收缩压持续升高有关。4. FSGS大鼠主动脉内皮细胞、血浆和尿液中的ADMA水平显著增加（P<0.05和P<0.005），但肾脏中的水平保持不变。5. 当用去甲肾上腺素和乙酰胆碱刺激时，FSGS大鼠有内皮的主动脉血管壁中环状GMP的基础水平和净生成量显著降低（P<0.05和P<0.01）。6. 内皮细胞（y=4.43x+122.2，r=0.979，P<0.0001）、血浆（y=0.10x+71.9，r=0.921，P<0.001）和尿液（y=0.48x+126.9，r =0.699，P<0.005）中的收缩压（y）与ADMA水平（x）之间存在显著正相关，但在肾脏中不显著（y=0.06x+102.7，r=0.252，无显著性差异）。7. 这些发现表明，ADMA作为一氧化氮合成的内源性抑制剂，可能在大鼠实验性FSGS相关高血压的发病机制中起重要作用。