Mechanisms of the paradoxical effect of L-Arginine on glomerulosclerosis in 5/6 nephrectomized rats

L-精氨酸对 5/6 肾切除大鼠肾小球硬化的反常作用机制

• 批准号: 10671014
• 负责人: NAKANISHI Takeshi
• 金额: $ 1.92万
• 依托单位: Hyogo College of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671014/
• 关键词: 5; 6 nephrectomized rats; L-arginine; nitric oxide; glomerulosclerosis; interstitial fibrosis; L-Arginine; Nitric oxide(NO); in situ hybridization; NO合成酵素(NOS); ecNOS; nNOS; 間質線維化

It has been still controversial whether L-Arginine (L-ARG) ameliorate or aggravate renal function and histopathological changes in several models of renal disease, as L-ARG is the substrate for nitric oxide(NO) synthase as well as the precursor of proline and polyamines which cause renal fibrosis. These ambiguous results might be attributed to the difference in the dose and period of L-ARG administered, and animal model used in each observation. Therefore, we tested the dose-dependent effect of L-ARG on mean blood pressure (MBP), 24 hour urinary excretion of protein (UP), NO metabolites (NOィイD3-(/)2ィエD3+NOィイD3-(/)3ィエD3) and cyclic GMP (cGMP), plasma asymmetrical dimethylarginine (ADMA), glomerular sclerosis index (SI) and % interstitial fibrosis area (%INT) in 5/6 nephrectomized SD rats. 5/6 nephrectomized SD rats were divided into 4 groups. 1) L-ARG 0.2g/kg/day (0.2gARG) 2) L-ARG 1g/kg/day (1gARG) 3) L-ARG 2g/kg/day (2gARG) 4) No administration of L-ARG (ARG(-)). Compared with ARG(-) MBP, UP and ADMA were significantly decreased and NOィイD3-(/)2ィエD3+NOィイD3-(/)3ィエD3, cGMP were significantly increased in 0.2gARG. SI and %INT were significantly increased in 2gARG and decreased in 0.2gARG. Small dose of L-ARG ameliorated glomeruiosclerosis and interstitial fibrosis while larger dose did not. SI,%INT and ADMA were inversely correlated with NOィイD3-(/)2ィエD3+NOィイD3-(/)3ィエD3. These data suggested that renal NO synthesis might attenuate glomerulosclerosis and interstitial fibrosis and the rise in ADMA and L-ARG might cause the decrease in NO.

L-精氨酸（L-Arginine，L-ARG）是一氧化氮合酶（nitric oxide synthase，NO）的底物，也是脯氨酸和多胺的前体，可引起肾脏纤维化，因此，L-ARG是否能改善或加重肾脏功能和肾脏病理改变一直存在争议。这些不明确的结果可能归因于L-ARG给药剂量和给药时间的差异以及每次观察中使用的动物模型。因此，我们检测了L-ARG对5/6肾切除SD大鼠的平均血压（MBP）、24小时尿蛋白排泄量（UP）、NO代谢产物（NO代谢产物D3-（/）2-D3+NO代谢产物D3-（/）3-D3）和环磷酸鸟苷（cGMP）、血浆不对称二甲基精氨酸（ADMA）、肾小球硬化指数（SI）和间质纤维化面积%（%INT）的剂量依赖性影响。5/6只SD大鼠肾切除后分为4组。1)L-ARG 0.2g/kg/天（0.2gARG）2）L-ARG 1g/kg/天（1gARG）3）L-ARG 2g/kg/天（2gARG）4）未给予L-ARG（ARG（-））。0.2gARG组与ARG（-）组比较，MBP、UP、ADMA显著降低，NO含量D3-（/）2、D3+NO含量D3-（/）3、D3、cGMP显著升高。SI和%INT在2gARG中显著增加，在0.2gARG中降低。小剂量L-ARG可减轻肾小球肾炎和间质纤维化，而大剂量L-ARG则无此作用。SI、%INT和ADMA与NO代谢D3-（/）2 β D3+NO代谢D3-（/）3 β D3呈负相关。提示肾组织NO的合成可减轻肾小球硬化和间质纤维化，ADMA和L-ARG的升高可能导致NO的减少。

项目成果

田中 俊彦、他: "5/6腎摘ラットにおけるL-ArginineのNO産生および糸球体組織に対する逆説的容量依存性効果"日本腎臓学会誌. 41(8). 754-763 (1999)

Toshihiko Tanaka 等人：“L-精氨酸对 5/6 肾切除大鼠的 NO 产生和肾小球组织的反常剂量依赖性影响”，日本肾病学会杂志 41(8) (1999)。

田中俊彦、他: "5/6腎摘ラットにおけるL-ArginineのNO産生および糸球体組織に対する逆説的容量依存性効果"日本腎臓学会誌.. 41(8). 754-763 (1999)

Toshihiko Tanaka 等人：“L-精氨酸对 5/6 肾切除大鼠的 NO 产生和肾小球组织的反常剂量依赖性影响”，日本肾病学会杂志 41(8) (1999)。