Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.