Yang Xiao-Ling, Chen Yan-Yan, Zhao Hua, Zhang Bo-Yang, Zhang Xiao-Fu, Li Xiao-Jie, Yang Xiu-Hong
School of Basic Medicine, North China University of Science and Technology, Tangshan 063000, China.
Hebei Key Laboratory of Basic Medicine for Chronic Diseases, Tangshan 063000, China.
Sheng Li Xue Bao. 2025 Jun 25;77(3):408-418. doi: 10.13294/j.aps.2025.0046.
This study aims to investigate the effects of renin inhibitor aliskiren on kidney injury in human angiotensinogen-renin (AGT-REN) double transgenic hypertensive (dTH) mice and explore its possible mechanism. The dTH mice were divided into hypertension group (HT group) and aliskiren intervention group (HT+Aliskiren group), while wild-type C57BL/6 mice were served as the control group (WT group). Blood pressure data of mice in HT+Aliskiren group were collected after 28 d of subcutaneous penetration of aliskiren (20 mg/kg), and the damage of renal tissue structure and collagen deposition were observed by HE, Masson and PAS staining. The ultrastructure of kidney was observed by transmission electron microscope. Coomassie bright blue staining and biochemical analyzer were used to detect renal function injury. The expression of renin-angiotensin system (RAS) was determined by ELISA and immunohistochemistry. The contents of superoxide dismutase (SOD) and malondialdehyde (MDA) in kidney were determined by chemiluminescence method. The content of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47, inducible nitric oxide synthase (iNOS), 3-nitrotyrosine (3-NT), NADPH oxidase 2 (NOX2) and NADPH oxidase 4 (NOX4) were detected by Western blot analysis. The results showed that compared with WT group, the blood pressure of mice in HT group was significantly increased. The renal tissue structure in HT group showed glomerular sclerosis, severe interstitial tubular injury, and increased collagen deposition. In addition, 24 h urinary protein, serum creatinine and urea levels increased. Serum and renal tissue levels of angiotensin II (Ang II) were increased, serum angiotensin-(1-7) [Ang-(1-7)] expression was decreased, and renal Ang-(1-7) expression was elevated. The expressions of ACE, Ang II type 1 receptor (ATR) and MasR in renal tissue were increased, while the expression of ACE2 was decreased. MDA content increased, SOD content decreased, and the expressions of p47, iNOS, 3-NT, NOX2 and NOX4 were increased. However, aliskiren reduced blood pressure in dTH mice, improved renal structure and renal function, reduced Ang II and Ang-(1-7) levels in serum and renal tissue, reduced the expression of ACE and ATR in renal tissue, increased the expression of ACE2 and MasR in renal tissue, and decreased the above levels of oxidative stress indexes in dTH mice. These results suggest that aliskiren may play a protective role in hypertensive renal injury by regulating the balance between ACE-Ang II-ATR and ACE2-Ang-(1-7)-MasR axes and inhibiting oxidative stress.
本研究旨在探讨肾素抑制剂阿利吉仑对人血管紧张素原-肾素（AGT-REN）双转基因高血压（dTH）小鼠肾损伤的影响，并探讨其可能机制。将dTH小鼠分为高血压组（HT组）和阿利吉仑干预组（HT+阿利吉仑组），野生型C57BL/6小鼠作为对照组（WT组）。阿利吉仑（20mg/kg）皮下渗透28d后收集HT+阿利吉仑组小鼠的血压数据，通过HE、Masson和PAS染色观察肾组织结构损伤及胶原沉积情况。用透射电子显微镜观察肾脏超微结构。采用考马斯亮蓝染色和生化分析仪检测肾功能损伤。通过ELISA和免疫组化法检测肾素-血管紧张素系统（RAS）的表达。采用化学发光法测定肾脏中超氧化物歧化酶（SOD）和丙二醛（MDA）的含量。通过蛋白质印迹分析检测烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶亚基p47、诱导型一氧化氮合酶（iNOS）、3-硝基酪氨酸（3-NT）、NADPH氧化酶2（NOX2）和NADPH氧化酶4（NOX4）的含量。结果显示，与WT组相比，HT组小鼠血压显著升高。HT组肾组织结构表现为肾小球硬化、严重的肾小管间质损伤及胶原沉积增加。此外，24h尿蛋白、血清肌酐和尿素水平升高。血清及肾组织中血管紧张素II（Ang II）水平升高，血清血管紧张素-（1-7）[Ang-（1-7）]表达降低，肾组织中Ang-（1-7）表达升高。肾组织中ACE、血管紧张素II 1型受体（ATR）和MasR的表达增加，而ACE2的表达降低。MDA含量增加，SOD含量降低，p47、iNOS、3-NT、NOX2和NOX4的表达增加。然而，阿利吉仑可降低dTH小鼠血压，改善肾脏结构和肾功能，降低血清及肾组织中Ang II和Ang-（1-7）水平，降低肾组织中ACE和ATR的表达，增加肾组织中ACE2和MasR的表达，并降低dTH小鼠上述氧化应激指标水平。这些结果表明，阿利吉仑可能通过调节ACE-Ang II-ATR与ACE2-Ang-（1-7）-MasR轴之间的平衡并抑制氧化应激，对高血压肾损伤发挥保护作用。
