Novel pharmacological approaches to the treatment of renal ischemia-reperfusion injury: a comprehensive review.
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.
Chatterjee
Prabal K
PK
Division of Pharmacology and Therapeutics, School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Lewes Road, Moulsecoomb, Brighton BN2 4GJ, UK. pkc1@bton.ac.uk
D058186:Acute Kidney Injury / Q000517:prevention & control; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D004921:Erythropoietin / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000098:blood supply*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D058906:Purinergic P1 Receptor Agonists; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000819:agonists; D011994:Recombinant Proteins; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism
D000975:Antioxidants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047492:Peroxisome Proliferator-Activated Receptors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D058906:Purinergic P1 Receptor Agonists; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D049349:Receptors, Lysosphingolipid; D011994:Recombinant Proteins; D004921:Erythropoietin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase