Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan 333031, India.
Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
Life Sci. 2019 Oct 15;235:116796. doi: 10.1016/j.lfs.2019.116796. Epub 2019 Aug 27.
Depressor arm of the renin-angiotensin system (RAS) exerts reno-protective effects in chronic kidney diseases like diabetic nephropathy. However, same is still elusive under AKI and hyperglycaemia comorbidity. Hence, the present study delineates the role of angiotensin-II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in AKI under normal and hyperglycaemia condition.
Non-diabetic (ND) and Streptozotocin-induced diabetes mellitus (DM) rats were subjected to ischemic renal injury (IRI). Rats underwent IRI were treated with an AT2R agonist, C21 (0.3 mg/kg/day, i.p.) or ACE2 activator, Dize, (5 mg/kg/day, p.o.) either alone or as combination therapy. Renal histopathology and immunohistochemistry, proximal tubular fraction isolation, ELISA, immunoblotting and qRT-PCR were performed for subsequent analysis.
Rats subjected to IRI displayed an increase in plasma ACE, AT1R, AT2R, Ang II, and reduction in ACE2, Ang-(1-7) expressions, with augmented renal inflammation and apoptosis. These changes were more prominent in diabetic rats with IRI. Co-administration of C21 and Dize augmented ACE2, Ang-(1-7), AT2R and MasR expressions, and attenuated tubular injury in both DM and ND rats.
We demonstrated that pharmacological activation of AT2R and ACE2 protects DM and ND rats from IRI by preventing oxidative stress, inflammation and apoptosis-mediated tubular damage.
肾素-血管紧张素系统（RAS）的抑制臂在糖尿病肾病等慢性肾脏病中发挥肾保护作用。然而，在急性肾损伤（AKI）和高血糖合并症的情况下，同样的作用仍然难以捉摸。因此，本研究描述了血管紧张素-II 型 2 型受体（AT2R）和血管紧张素转换酶 2（ACE2）在正常和高血糖条件下 AKI 中的作用。
非糖尿病（ND）和链脲佐菌素诱导的糖尿病（DM）大鼠进行缺血性肾损伤（IRI）。IRI 大鼠用 AT2R 激动剂 C21（0.3mg/kg/天，腹腔注射）或 ACE2 激活剂 Dize（5mg/kg/天，口服）单独或联合治疗。进行肾组织病理学和免疫组织化学、近端肾小管分离、ELISA、免疫印迹和 qRT-PCR 分析。
IRI 大鼠的血浆 ACE、AT1R、AT2R、Ang II 增加，ACE2、Ang-（1-7）表达减少，伴有肾炎症和细胞凋亡增加。这些变化在糖尿病伴 IRI 的大鼠中更为明显。C21 和 Dize 的联合给药增加了 ACE2、Ang-（1-7）、AT2R 和 MasR 的表达，并减轻了 DM 和 ND 大鼠的肾小管损伤。
我们证明了 AT2R 和 ACE2 的药理学激活通过预防氧化应激、炎症和细胞凋亡介导的肾小管损伤，保护 DM 和 ND 大鼠免受 IRI。
