H(2)S inhibits hyperglycemia-induced intrarenal renin-angiotensin system activation via attenuation of reactive oxygen species generation.
H(2)S inhibits hyperglycemia-induced intrarenal renin-angiotensin system activation via attenuation of reactive oxygen species generation.
复制标题
H2S 通过减弱活性氧的产生来抑制高血糖诱导的肾素-血管紧张素系统激活
DOI：
10.1371/journal.pone.0074366
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Xue H;Yuan P;Ni J;Li C;Shao D;Liu J;Shen Y;Wang Z;Zhou L;Zhang W;Huang Y;Yu C;Wang R;Lu L
内源性硫化氢(H_2S)减少被认为参与了糖尿病肾病(DN)的发病过程。本研究旨在探讨H_2S代谢异常、高血糖所致的氧化应激与肾素-血管紧张素系统(RAS)激活的关系。采用体外培养的肾小球系膜细胞(MCs)和链脲佐菌素(STZ)诱导的糖尿病大鼠。用实时荧光定量聚合酶链式反应和免疫印迹法检测血管紧张素原、血管紧张素转换酶、血管紧张素ⅡI型受体、转化生长因子-β1和IV型胶原的表达。用荧光探针法测定细胞内活性氧(ROS)生成。5‘-溴-2’-脱氧尿嘧啶核苷掺入法检测细胞增殖。用酶免疫法测定血管紧张素Ⅱ浓度。高糖处理后，血管紧张素Ⅱ、血管紧张素转换酶、血管紧张素转换酶和血管紧张素Ⅱ受体基因表达增加，细胞增殖率增加，转化生长因子-β-1和IV型胶原生成增加。NADPH氧化酶抑制剂二苯氯碘(DPI)能逆转HG诱导的RAS激活及细胞增殖和胶原合成的变化。补充H_2S可减弱HG诱导的ROS和RAS活性的升高。用丙叉甘氨酸阻断半胱硫酮-γ-裂解酶合成H_2S的效果与HG处理相似。在STZ诱导的糖尿病大鼠中，补充硫化氢也逆转了RAS的变化，而不影响血糖浓度。这些数据表明，高血糖条件下H_2S的减少导致了氧化和还原物种之间的失衡。氧化物种的增加导致肾内RAS的激活，进而导致肾功能障碍的发生。
Decrease in endogenous hydrogen sulfide (H2S) was reported to participate in the pathogenesis of diabetic nephropathy (DN). This study is aimed at exploring the relationship between the abnormalities in H2S metabolism, hyperglycemia-induced oxidative stress and the activation of intrarenal renin-angiotensin system (RAS). Cultured renal mesangial cells (MCs) and streptozotocin (STZ) induced diabetic rats were used for the studies. The expressions of angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II (Ang II) type I receptor (AT1), transforming growth factor-β1 (TGF-β1) and collagen IV were measured by real time PCR and Western blot. Reactive oxygen species (ROS) production was assessed by fluorescent probe assays. Cell proliferation was analyzed by 5'-bromo-2'-deoxyuridine incorporation assay. Ang II concentration was measured by an enzyme immunoassay. AGT, ACE and AT1 receptor mRNA levels and Ang II concentration were increased in high glucose (HG) -treated MCs, the cell proliferation rate and the production of TGF-β1 and of collagen IV productions were also increased. The NADPH oxidase inhibitor diphenylenechloride iodonium (DPI) was able to reverse the HG-induced RAS activation and the changes in cell proliferation and collagen synthesis. Supplementation of H2S attenuated HG-induced elevations in ROS and RAS activation. Blockade on H2S biosynthesis from cystathione-γ-lyase (CSE) by DL-propargylglycine (PPG) resulted in effects similar to that of HG treatment. In STZ-induced diabetic rats, the changes in RAS were also reversed by H2S supplementation without affecting blood glucose concentration. These data suggested that the decrease in H2S under hyperglycemic condition leads to an imbalance between oxidative and reductive species. The increased oxidative species results in intrarenal RAS activation, which, in turn, contributes to the pathogenesis of renal dysfunction.