补充L-精氨酸会加速实验性狼疮性肾炎的肾纤维化并缩短寿命。

L-arginine supplementation accelerates renal fibrosis and shortens life span in experimental lupus nephritis.

作者信息

Peters Harm, Border Wayne A, Rückert Matthias, Krämer Stephanie, Neumayer Hans-H, Noble Nancy A

机构信息

Division of Nephrology, Charité, Campus Mitte, Humboldt-University Berlin, Germany.

出版信息

Kidney Int. 2003 Apr;63(4):1382-92. doi: 10.1046/j.1523-1755.2003.00881.x.

DOI:10.1046/j.1523-1755.2003.00881.x

PMID:12631354

Abstract

BACKGROUND

Inducible, high-output nitric oxide (NO) production has been identified as a central mediator of cell injury in immune-mediated renal disease. In acute anti-thy-1 glomerulonephritis prefeeding with the NO precursor L-arginine increases mesangial cell injury and the subsequent fibrosis. The present study tested the hypothesis that L-arginine supplementation may also be detrimental in chronic, NO-mediated murine lupus nephritis.

METHODS

Groups (N = 18) of female MRL/lpr mice with lupus nephritis were fed the following diets: (1) normal protein (22% casein); (2) normal protein and 1.0% L-arginine in the drinking water; (3) low protein (6% casein); (4) low protein + 0.4%l-arginine; and (5) low protein + 1.0% L-arginine. After 40 days mouse survival, albuminuria, matrix accumulation, inflammatory cell infiltration, immunoglobulin G (IgG) deposition, expression of transforming growth factor-beta 1 (TGF-beta 1), fibronectin and plasminogen activator inhibitor-1 (PAI-1) mRNA and protein, anti-DNA antibody titer, inducible nitric oxide synthase (iNOS) mRNA expression, blood amino acid levels, blood urea nitrogen (BUN) concentrations and blood and urinary NOx (nitrite + nitrate) levels were assessed.

RESULTS

L-Arginine supplementation increased mortality significantly (P < 0.02). The death rate increased from 0% in the lowest to 50% in the highest L-arginine intake group (normal protein + 1.0% L-arginine). L-Arginine administration increased albuminuria, renal matrix accumulation, TGF-beta 1, fibronectin, PAI-1, blood L-arginine, L-citrulline, BUN and blood and urine NOx levels, while protein restriction reduced these parameters. Renal cell infiltration and iNOS mRNA expression were decreased in the low protein group only. Anti-ds DNA-IgG and renal IgG deposition were comparable in all groups

CONCLUSIONS

Increasing L-arginine intake increases the severity of renal fibrosis and the likelihood of death in MRL/lpr mice. The results appear to be at least in part mediated through enhanced cytotoxic NO generation via iNOS. The data suggest that L-arginine restriction should be considered in human immune-mediated renal diseases.

摘要

背景

诱导性高产量一氧化氮（NO）生成已被确定为免疫介导性肾脏疾病中细胞损伤的主要介质。在急性抗 Thy-1 肾小球肾炎中，预先给予 NO 前体 L-精氨酸会增加系膜细胞损伤及随后的纤维化。本研究检验了以下假设：补充 L-精氨酸在慢性 NO 介导的小鼠狼疮性肾炎中可能也有害。

方法

将患有狼疮性肾炎的雌性 MRL/lpr 小鼠分为几组（每组 N = 18 只），给予以下饮食：（1）正常蛋白质（22% 酪蛋白）；（2）正常蛋白质且饮用水中含 1.0% L-精氨酸；（3）低蛋白质（6% 酪蛋白）；（4）低蛋白质 + 0.4% L-精氨酸；（5）低蛋白质 + 1.0% L-精氨酸。40 天后，评估小鼠存活率、蛋白尿、基质积聚、炎性细胞浸润、免疫球蛋白 G（IgG）沉积、转化生长因子-β1（TGF-β1）、纤连蛋白和纤溶酶原激活物抑制剂-1（PAI-1）mRNA 及蛋白表达、抗 DNA 抗体滴度、诱导型一氧化氮合酶（iNOS）mRNA 表达、血液氨基酸水平、血尿素氮（BUN）浓度以及血液和尿液中 NOx（亚硝酸盐 + 硝酸盐）水平。

结果

补充 L-精氨酸显著增加死亡率（P < 0.02）。死亡率从最低 L-精氨酸摄入量组的 0% 增加到最高 L-精氨酸摄入量组（正常蛋白质 + 1.0% L-精氨酸）的 50%。给予 L-精氨酸会增加蛋白尿、肾基质积聚、TGF-β1、纤连蛋白、PAI-1、血液 L-精氨酸、L-瓜氨酸、BUN 以及血液和尿液中 NOx 水平，而蛋白质限制可降低这些参数。仅低蛋白质组的肾细胞浸润和 iNOS mRNA 表达降低。所有组的抗双链 DNA-IgG 和肾 IgG 沉积相当。