Research & Development Unit, Assaf Harofeh Medical Center, Zerifin 70300, Tel Aviv University, Israel.
Nephrol Dial Transplant. 2012 Jan;27(1):136-45. doi: 10.1093/ndt/gfr256. Epub 2011 Jun 16.
Ischemia/reperfusion triggers acute kidney injury (AKI), mainly via aggravating hypoxia, oxidative stress, inflammation and renin-angiotensin system (RAS) activation. We investigated the role of angiotensin-converting enzyme (ACE) inhibition on the progression of AKI in a rat model of ischemia/reperfusion.
Ninety-nine Sprague-Dawley rats were subjected to 1 h ischemia/reperfusion and/or left unilateral nephrectomy, with concurrent intraperitoneal implantation of Alzet pump. Via this pump, they were continuously infused with captopril 0.5 mg/kg/day, captopril 2 mg/kg/day or saline. The rats were sacrificed following 24, 48 or 168 h. Blood samples, 24-h urine collections and kidneys were allocated, to evaluate renal function, angiotensin-II, nitric oxide (NO), apoptosis, hypoxia, oxidative stress and inflammation.
Serum creatinine and cystatin-C significantly increased in ischemic rats, coinciding with histopathologic intrarenal damage, decreased NO, augmented angiotensin-II, interleukin (IL)-6, IL-10, transforming growth factor-beta. At the acute reperfusion stage, captopril prevented excessive angiotensin-II synthesis, ameliorated renal dysfunction, inhibited intrarenal inflammation and improved histopathologic findings. Most of the renoprotective effects of captopril were limited predominantly to acute reperfusion stage. Concurrently, captopril significantly decreased NO availability, exacerbated intrarenal hypoxia and augmented oxidative stress.
At the acute stage of renal ischemia/reperfusion-induced AKI, ACE inhibition substantially contributed to the amelioration of acute injury by improving renal function, inhibiting systemic and intrarenal angiotensin-II, attenuating intrarenal inflammation and preserving renal tissue structure. Later on, at the post-reperfusion stage, most of the beneficial effects of captopril administration on the recuperating post-ischemic kidney were no longer evident. Concurrently, ACE inhibition exacerbated intrarenal hypoxia and accelerated oxidative stress, indicating that renal adaptation to some consequences of ischemia does require bioavailability of RAS components.
缺血/再灌注会引发急性肾损伤（AKI），主要通过加重缺氧、氧化应激、炎症和肾素-血管紧张素系统（RAS）激活来实现。我们在缺血/再灌注大鼠模型中研究了血管紧张素转换酶（ACE）抑制对 AKI 进展的作用。
99 只 Sprague-Dawley 大鼠接受 1 小时缺血/再灌注和/或单侧肾切除术，并同时进行腹腔内 Alzet 泵植入。通过该泵，大鼠持续输注卡托普利 0.5mg/kg/天、卡托普利 2mg/kg/天或生理盐水。24、48 或 168 小时后处死大鼠。收集血液样本、24 小时尿液和肾脏，评估肾功能、血管紧张素-II、一氧化氮（NO）、细胞凋亡、缺氧、氧化应激和炎症。
缺血大鼠血清肌酐和胱抑素-C 显著升高，同时伴有肾内组织病理学损伤、NO 减少、血管紧张素-II、白细胞介素（IL）-6、IL-10、转化生长因子-β增加。在急性再灌注阶段，卡托普利可防止血管紧张素-II过度合成，改善肾功能，抑制肾内炎症，改善组织病理学发现。卡托普利的大部分肾保护作用主要局限于急性再灌注阶段。同时，卡托普利显著降低了 NO 的可利用性，加重了肾内缺氧，并增强了氧化应激。
在肾缺血/再灌注诱导的 AKI 的急性阶段，ACE 抑制通过改善肾功能、抑制全身和肾内血管紧张素-II、减轻肾内炎症和保护肾组织结构，对急性损伤的改善有很大的作用。后来，在再灌注后期，卡托普利对缺血后恢复肾脏的大部分有益作用不再明显。同时，ACE 抑制加重了肾内缺氧并加速了氧化应激，表明肾脏对某些缺血后果的适应确实需要 RAS 成分的生物利用度。
