Novel pharmacological approaches to the treatment of renal ischemia-reperfusion injury: a comprehensive review

Abstract

Renal ischemia-reperfusion (I-R) contributes to the development of ischemic acute renal failure (ARF). Multi-factorial processes are involved in the development and progression of renal I-R injury with the generation of reactive oxygen species, nitric oxide and peroxynitrite, and the decline of antioxidant protection playing major roles, leading to dysfunction, injury, and death of the cells of the kidney. Renal inflammation, involving cytokine/adhesion molecule cascades with recruitment, activation, and diapedesis of circulating leukocytes is also implicated. Clinically, renal I-R occurs in a variety of medical and surgical settings and is responsible for the development of acute tubular necrosis (a characteristic feature of ischemic ARF), e.g., in renal transplantation where I-R of the kidney directly influences graft and patient survival. The cellular mechanisms involved in the development of renal I-R injury have been targeted by several pharmacological interventions. However, although showing promise in experimental models of renal I-R injury and ischemic ARF, they have not proved successful in the clinical setting (e.g., atrial natriuretic peptide, low-dose dopamine). This review highlights recent pharmacological developments, which have shown particular promise against experimental renal I-R injury and ischemic ARF, including novel antioxidants and antioxidant enzyme mimetics, nitric oxide and nitric oxide synthase inhibitors, erythropoietin, peroxisome-proliferator-activated receptor agonists, inhibitors of poly(ADP-ribose) polymerase, carbon monoxide-releasing molecules, statins, and adenosine. Novel approaches such as recent research involving combination therapies and the potential of non-pharmacological strategies are also considered.

The Protective Effects of Ascorbic Acid against Renal Ischemia-Reperfusion Injury in Male Rats

“…Previous experiments show that various exogenous antioxidant agents such as allopurinol, melatonin, tocopherol, leflunomide, and some flavonoids have the potential to reduce I/R induced-renal injury and help the improvement of kidney function. [10,[13][14][15]26] In this study, we used AA as an exogenous antioxidant. AA is one of the water-soluble vitamins and is well known as a strong antioxidant agent.…”

“…[9] Experimentally, various agents such as novel antioxidants, antioxidant enzymes mimetics, flavonoids, nitric oxide synthase inhibitors, erythropoietin, peroxisome-proliferator-activated receptor agonists, erythropoietin, statins, adenosine, and calcium channel blockers were used to prevent kidney from I/R injury. [10] Many studies have shown that these antioxidants act as renoprotective against I/R induced cell damage. It has been demonstrated in dogs that pretreatment with allopurinol improves post-transplantation renal function and graft survival.…”

Betulinic acid protects against ischemia/reperfusion‐induced renal damage and inhibits leukocyte apoptosis

“…Although many have been evaluated clinically with a view to reducing renal I/R injury and improving renal function, none has been able to reduce mortality signifi cantly. I/R induced organ damage is multifactorial and interdependent, involving hypoxia, infl ammatory responses and free radical damage (Weight et al, 1996;Chatterjee, 2007;Boros and Bromberg, 2006). Thus, agents with antioxidant and antiinfl ammatory effects are thought to be useful in the clinical setting of I/R damage.…”

“…However, in ischemia the depletion of energy stores and also the initiation of lipid peroxidation due to increased free radicals following reperfusion causes inhibition of membrane Na + ,K + -ATPase activity (Matsuzaki et al, 2007;Ş ehirli et al, 2008). Thus I/R-induced ARF, characterized by impaired renal function, reduced glomerular fi ltration and tubular sodium reabsorption have been related to the functional disorders of Na + ,K + -ATPase (Chatterjee, 2007). In agreement with these investigations, in our study there was a signifi cant decrease in the activity of Na + ,K + -ATPase in the saline treated I/R group, while BA treatment restored the enzyme activity possibly protecting the membrane structure by its antioxidant effect.…”

“…Biological compounds with antioxidant properties may contribute to the protection of cells and tissues against the deleterious effects of reactive oxygen species (ROS) and other free radicals induced by I/R (Granger and Korthuis, 1995;Chatterjee, 2007). However, the structure-activity relationship, bioavailability and therapeutic effi cacy differ extensively.…”