Mei Xi, Zeng Jun, Liu Dong-Fang, Zhao Ye, Yang Hui-Lan, Li Yao, Qiu Ping, Tang Ming-Wei
Department of Endocrinology and Metabolism, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
School of Bioscience and Technology, Chengdu Medical College, Chengdu, China.
Ann Palliat Med. 2021 Mar;10(3):3343-3353. doi: 10.21037/apm-21-417.
Symmetrical dimethylarginine (ADMA) endogenously inhibits nitric oxide synthase (NOS) and strongly indicates oxidant stress, whose formation primarily derived from type 1 protein arginine N-methyltransferase (PRMT1) and whose metabolism was governed by type 1 dimethylarginine dimethylaminohydrolase (DDAH1). This study aimed to evaluate participation of the PRMT1-ADMA-DDAH1 metabolism axis in the kidneys of type 2 diabetes model rats and human subjects, and the effect of probucol on this axis and renal function.
A total of 30 rats were randomly assigned to a normal group (NC, n=10), diabetic group (DM, n=10), and a diabetics under probucol treatment group (PM, n=10). Throughout 8 weeks of probucol treatment, plasma NOS, the malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO), and catalase (CAT) activity were evaluated by chemical colorimetric approach. ADMA concentration was evaluated with an enzyme-linked immunosorbent assay (ELISA) and analysis of expression of PRMT1 and DDAH1 in kidneys with reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC) and western blotting were performed.
The expression of DDAH1 in the kidney, and the plasma NOS, NO, SOD, and CAT activities in diabetic group were lower, while MDA and the expression of PRMT1 and ADMA were higher in contrast to the control group. In diabetics rats receiving probucol, the expressions of DDAH1 and ADMA were downregulated, whereas that of PRMT1 was upregulated. Probucol inhibited the indexes of oxidative stress and improved the kidney function in both diabetic rats and humans.
We found that the expression of the PRMT1-ADMA-DDAH1 axis was altered in the kidneys of diabetic rats. Moreover, results indicated that probucol therapy regulates expression at both ends of this axis, which may preserve renal function by reducing oxidant stress. Therefore, probucol may partially restore expression of the PRMT1-ADMA-DDAH1 axis in diabetic kidneys, immigrate oxidant stress, and enhance renal function.
对称二甲基精氨酸（ADMA）可内源性抑制一氧化氮合酶（NOS），并强烈提示氧化应激，其形成主要源于1型蛋白质精氨酸N-甲基转移酶（PRMT1），其代谢受1型二甲基精氨酸二甲胺水解酶（DDAH1）调控。本研究旨在评估PRMT1-ADMA-DDAH1代谢轴在2型糖尿病模型大鼠和人类受试者肾脏中的参与情况，以及普罗布考对该轴和肾功能的影响。
将30只大鼠随机分为正常组（NC，n = 10）、糖尿病组（DM，n = 10）和普罗布考治疗的糖尿病组（PM，n = 10）。在普罗布考治疗的8周期间，采用化学比色法评估血浆NOS、丙二醛（MDA）、超氧化物歧化酶（SOD）、一氧化氮（NO）和过氧化氢酶（CAT）活性。采用酶联免疫吸附测定（ELISA）评估ADMA浓度，并通过逆转录-聚合酶链反应（RT-PCR）、免疫组织化学（IHC）和蛋白质印迹法分析肾脏中PRMT1和DDAH1的表达。
与对照组相比，糖尿病组肾脏中DDAH1的表达以及血浆NOS、NO、SOD和CAT活性较低，而MDA以及PRMT1和ADMA的表达较高。在接受普罗布考治疗的糖尿病大鼠中，DDAH1和ADMA的表达下调，而PRMT1的表达上调。普罗布考抑制了氧化应激指标并改善了糖尿病大鼠和人类的肾功能。
我们发现糖尿病大鼠肾脏中PRMT1-ADMA-DDAH1轴的表达发生了改变。此外，结果表明普罗布考治疗可调节该轴两端的表达，这可能通过降低氧化应激来保护肾功能。因此，普罗布考可能部分恢复糖尿病肾脏中PRMT1-ADMA-DDAH1轴的表达，减轻氧化应激，并增强肾功能。
