Department of Pharmacology, ISF College of Pharmacy, Moga, India.
Department of Pharmacology, ISF College of Pharmacy, Moga, India.
Exp Gerontol. 2020 Jul 1;135:110892. doi: 10.1016/j.exger.2020.110892. Epub 2020 Feb 28.
Ischemia/reperfusion (I/R) injury is a common cause of acute kidney injury (AKI), which occurs clinically during renal organ transplantation and major cardiac surgeries. Previously, it was demonstrated that angiotensin II type 1 receptor (AT) receptor antagonism is beneficial in the resolution of AKI episodes in young rats by reducing inflammation and oxidative stress. However, studies have shown that aged kidneys are refractory to surgical ischemic pre-conditioning due to increased oxidative stress, mitochondrial dysfunction, inflammation and apoptosis. Therefore, the present study was designed to evaluate the effects of pharmacologically induced pre-conditioning on I/R induced AKI in aged kidneys.
AKI was induced by clamping both renal pedicels for 45 min followed by 24 h of reperfusion. The AT receptor antagonist, losartan was administered for three days prior to I/R injury induction in both aged and young rats. Renal outcomes were assessed by serum creatinine, creatinine clearance and proteinuria, renal antioxidant enzyme assays, membrane NaKATPase activity, inflammatory biomarkers, and histological studies.
AKI developed 24 h post ischemia, as indicated by elevated serum creatinine levels, proteinuria, oxidative stress, reduced membrane NaKATPase activity, increased inflammatory biomarkers levels and histological damage including cellular infiltration, tubular thickening, tubular dilation and necrosis. Losartan pre-treatment significantly improved renal dysfunction and histological alterations in young rats subjected to I/R injury. However, this treatment did not prevent various AKI manifestations in aged rats due to elevated oxidative and inflammatory stress mediated via tubular dysfunction and damage.
We conclude that AT receptor antagonism is not beneficial against renal I/R induced AKI in aged rats.
缺血/再灌注（I/R）损伤是急性肾损伤（AKI）的常见原因，在肾器官移植和大心脏手术中临床会发生这种损伤。先前的研究表明，血管紧张素 II 型 1 型受体（AT）受体拮抗作用通过减少炎症和氧化应激，有利于年轻大鼠 AKI 发作的缓解。然而，研究表明，由于氧化应激、线粒体功能障碍、炎症和细胞凋亡增加，老年肾脏对手术缺血预处理具有抗性。因此，本研究旨在评估药物诱导预处理对老年肾脏 I/R 诱导的 AKI 的影响。
夹闭双侧肾蒂 45 分钟，然后再灌注 24 小时，诱导 AKI。在 I/R 损伤诱导前，在年轻和老年大鼠中连续三天给予 AT 受体拮抗剂氯沙坦。通过血清肌酐、肌酐清除率和蛋白尿、肾抗氧化酶测定、膜 NaKATP 酶活性、炎症生物标志物和组织学研究评估肾脏结局。
缺血 24 小时后发生 AKI，表现为血清肌酐水平升高、蛋白尿、氧化应激、膜 NaKATP 酶活性降低、炎症生物标志物水平升高和组织学损伤，包括细胞浸润、肾小管增厚、肾小管扩张和坏死。氯沙坦预处理可显著改善年轻大鼠 I/R 损伤后的肾功能和组织学改变。然而，由于肾小管功能障碍和损伤导致的氧化和炎症应激增加，这种治疗方法并不能预防老年大鼠各种 AKI 表现。
我们得出结论，AT 受体拮抗作用对老年大鼠肾 I/R 诱导的 AKI 无益。
