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.

在几种肾脏疾病模型中，L-精氨酸（L-ARG）改善或加重肾功能和组织病理学变化仍然存在争议，因为L-ARG是一氧化物（NO）合酶以及引起肾纤维化的脯氨酸和多胺的前体的底物。这些模棱两可的结果可能归因于施用L-ARG的剂量和周期的差异，以及在每个观察结果中使用的动物模型。 Therefore, we tested the dose-dependent effect of L-ARG on mean blood pressure (MBP), 24 hour urinary extremes of protein (UP), NO metabolites (NOI D3-(/)2E D3+NOI D3-(/)3E D3) and cyclic GMP (cGMP), plasma asymmetrical dimethylarginine (ADMA), glomerular sclerosis index (SI) 5/6肾切除型SD大鼠中的间质纤维化区域（％INT）。将5/6个肾切除的SD大鼠分为4组。 1）l-arg 0.2g/kg/day（0.2garg）2）l-arg 1g/kg/day（1garg）3）l-arg 2g 2g 2g/kg/day（2garg）4）l-arg（arg（ - ））不给予L-arg（arg（ - ））。与ARG（ - ）MBP相比，UP和ADMA显着降低，NOII D3 - （/）2E D3+NOI D3 - （/）3E D3，CGMP在0.2GARG中显着增加。 2GARG中的Si和％INT显着增加，0.2GARG的降低。小剂量的L-Arg改善了肾小球硬化和间质性纤维化，而较大剂量则没有。 Si，％INT和ADMA与NOII D3 - （/）2IE D3+NOI D3 - （/）3IE D3成反比。这些数据表明，肾脏不合成可能会减弱肾小球硬化和间质纤维化，而ADMA和L-ARG的增加可能会导致NO中的减少。

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)。