Captopril and Ischemia/Reperfusion-induced AKI
Captopril and Ischemia/Reperfusion-induced AKI
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.
Acute kidney injury (AKI) is one of the main causes for the development of long-term chronic kidney disease. In the majority of cases, the prerequisite for AKI development is renal ischemia and consequent hemodynamic instability, as evidenced by altered renal blood flow and renal vascular resistance. Ischemia, and the following reperfusion, triggers renal dysfunction mainly by augmenting intrarenal hypoxia, inducing oxidative stress, aggravating inflammation and activating the renin–angiotensin system (RAS). Renal tubular tissue is particularly vulnerable to ischemia-induced hypoxic injury. Oxidative stress, the direct consequence of hypoxia, is exacerbated further during reperfusion. Inflammation triggered by ischemia is also amplified further by progression of intrarenal hypoxia: synthesis of proinflammatory cytokines is augmented, whereas production of anti-inflammatory factors becomes impaired, making the anti-inflammatory treatments ineffective. Local RAS contributes to the progression of ischemia-induced renal injury, mostly via augmented intrarenal angiotensin-II production. Increased angiotensin-II may further enhance inflammation, hypercellularity, apoptosis, reactive oxygen species formation and alter nitric oxide (NO) availability. Angiotensin-II is also a specific stimulator of renal mesangial cell proliferation and/or apoptosis.
Inhibition of RAS is the cornerstone of therapy for patients with chronic renal disease. There is ample evidence to suggest that suppression of RAS ameliorates deterioration of renal functioning via reduced intraglomerular pressure, decreased proteinuria, inhibited interstitial inflammation and antifibrotic effects. Long-term beneficial effects of RAS inhibition on kidney function have been demonstrated in patients with chronic renal injury. However, the role played by RAS blockade in acute renal events has not been thoroughly studied, except a limited number of papers investigating nephroprotective effects of angiotensin-II receptor blockers (ARB) in a model of AKI.
The mechanism of RAS inhibition by ARB is principally different from RAS suppression by administration of angiotensin-converting enzyme inhibitors (ACEi). Namely, ARBs prevent the entrance of the already produced angiotensin-II into the cell via its specific receptors, whereas ACEi abrogate the process of angiotensin-II synthesis per se. Nonetheless, the effects of ACEi administration on progression of AKI have not been studied in-depth. In particular, any information on the effects of angiotensin-converting enzyme (ACE) inhibition on patients or animals developing AKI as a result of ischemia/reperfusion-induced kidney injury is lacking.
We hypothesized RAS inhibition by ACEi in the context that AKI might exert nephroprotective effects. In the present study, we investigated the impacts of RAS inhibition by ACEi administration on renal function of rats subjected to AKI in a model of experimental ischemia/reperfusion. The effects of ACEi on intrarenal hypoxia, NO bioavailability, oxidative stress and inflammation were concomitantly assessed.
Abstract and Introduction
Abstract
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.
Introduction
Acute kidney injury (AKI) is one of the main causes for the development of long-term chronic kidney disease. In the majority of cases, the prerequisite for AKI development is renal ischemia and consequent hemodynamic instability, as evidenced by altered renal blood flow and renal vascular resistance. Ischemia, and the following reperfusion, triggers renal dysfunction mainly by augmenting intrarenal hypoxia, inducing oxidative stress, aggravating inflammation and activating the renin–angiotensin system (RAS). Renal tubular tissue is particularly vulnerable to ischemia-induced hypoxic injury. Oxidative stress, the direct consequence of hypoxia, is exacerbated further during reperfusion. Inflammation triggered by ischemia is also amplified further by progression of intrarenal hypoxia: synthesis of proinflammatory cytokines is augmented, whereas production of anti-inflammatory factors becomes impaired, making the anti-inflammatory treatments ineffective. Local RAS contributes to the progression of ischemia-induced renal injury, mostly via augmented intrarenal angiotensin-II production. Increased angiotensin-II may further enhance inflammation, hypercellularity, apoptosis, reactive oxygen species formation and alter nitric oxide (NO) availability. Angiotensin-II is also a specific stimulator of renal mesangial cell proliferation and/or apoptosis.
Inhibition of RAS is the cornerstone of therapy for patients with chronic renal disease. There is ample evidence to suggest that suppression of RAS ameliorates deterioration of renal functioning via reduced intraglomerular pressure, decreased proteinuria, inhibited interstitial inflammation and antifibrotic effects. Long-term beneficial effects of RAS inhibition on kidney function have been demonstrated in patients with chronic renal injury. However, the role played by RAS blockade in acute renal events has not been thoroughly studied, except a limited number of papers investigating nephroprotective effects of angiotensin-II receptor blockers (ARB) in a model of AKI.
The mechanism of RAS inhibition by ARB is principally different from RAS suppression by administration of angiotensin-converting enzyme inhibitors (ACEi). Namely, ARBs prevent the entrance of the already produced angiotensin-II into the cell via its specific receptors, whereas ACEi abrogate the process of angiotensin-II synthesis per se. Nonetheless, the effects of ACEi administration on progression of AKI have not been studied in-depth. In particular, any information on the effects of angiotensin-converting enzyme (ACE) inhibition on patients or animals developing AKI as a result of ischemia/reperfusion-induced kidney injury is lacking.
We hypothesized RAS inhibition by ACEi in the context that AKI might exert nephroprotective effects. In the present study, we investigated the impacts of RAS inhibition by ACEi administration on renal function of rats subjected to AKI in a model of experimental ischemia/reperfusion. The effects of ACEi on intrarenal hypoxia, NO bioavailability, oxidative stress and inflammation were concomitantly assessed.
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