Renoprotective mechanisms of ischemic postconditioning in ischemia–reperfusion injury: improved mitochondrial function and integrity

Acute kidney injury (AKI) can develop in up to 1 in 5 hospitalized patients, and despite advances in dialysis technique and clinical care, the prevalence of AKI continues to rise [1, 2]. In addition to being associated with a significantly increased risk of morbidity and mortality, AKI may also lead to the development of chronic kidney disease (CKD) or the progression of pre-existing CKD [3, 4]. Therefore, the development of strategies aimed at preventing AKI and improving the recovery rate once AKI has occurred are of significant clinical and therapeutic value. Clinically, AKI is defined as a sudden (within 48 h) decrease in renal function and can be caused by a broad range of pathophysiologic processes. Within this broad group of conditions, acute tubular necrosis (ATN) is the leading cause of AKI in hospitalized patients once volume depletion has been ruled out. Ischemic and nephrotoxic injuries to the tubules are the major causes of ATN in native and transplanted kidneys [5, 6]. Renal ischemia–reperfusion injury (IRI) can occur in patients with decreased renal perfusion in a variety of circumstances such as sepsis, heart failure or cardiovascular surgery. Under these circumstances, reperfusion relieves ischemia; however, it also leads to a cascade of adverse events that lead to the initiation and progression of renal injury. Multiple processes are involved in IRI including dysfunctional ion transport, dissipation of mitochondrial membrane potential, reactive oxygen species (ROS) generation, endothelial cell dysfunction, platelet aggregation, vascular constriction with decreased blood flow as well as immune activation and inflammation [7, 8]. Among the possible therapeutic interventions being explored to prevent the development and progression of AKI, ‘organ conditioning’ has become an area of special interest. The beneficial impact of organ conditioning was first described by Murry et al. [9] who found that brief, intermittent episodes of ischemia followed by resumption of perfusion prior to the prolonged ischemic insult had a protective effect on the myocardium and reduced myocradial infraction size in an animal model of cardiac IRI. This phenomenon became known as ischemic preconditioning (IPC), and there are numerous studies that have confirmed the renoprotective effect of IPC in ischemia–reperfusion models of renal injury [10]. Although poorly understood, it is believed that IPC's renoprotective properties are mediated through many different mechanisms including increased nitric oxide production and level, reduced inflammation and activation of protein kinase C and G(i/o) signaling pathways [11]. However, utility of IPC in the clinical setting is limited given that use of this intervention requires knowledge of when an ischemic insult will take place. While this can be predicted under some circumstances (i.e. elective cardiovascular surgery), in the majority of clinical situations, the onset of a renal ischemic insult is difficult to predict. Hence, application of IPC remains restricted to experimental studies or selective clinical cases, where a renal ischemic episode can be predicted. A more clinically applicable conditioning approach would be to develop interventions that can be applied at early reperfusion. Since this time point is easier to define and can be anticipated, these interventions would be more relevant and have a greater clinical applicability. In this regard, Zhao et al. [12] have demonstrated that repetitive ischemia applied during the early reperfusion period is as effective in reducing infarct size and preserving endothelial function as IPC in an animal model of myocardial IRI. This so called ischemic postconditioning (POC) has been studied extensively in various organs with mostly promising results [12]. In addition, POC has been studied and shown to have significant therapeutic potential in several animal models of renal IRI [13]. POC has been shown to improve renal function, substantially reduce histologic damage and significantly reduce apoptosis, interstitial fibrosis and inflammation in animal models of renal IRI [13]. Multiple mechanisms account for the renoprotective effects of POC in renal IRI. POC has been shown to lower markers of oxidative stress and ROS (i.e. malondialdehyde) while increasing antioxidant enzymes and molecules (i.e. superoxide dismutase, glutathione, glutathione peroxidase and catalase) [13]. Another important mechanism by which POC confers protection against ischemia–reperfusion renal injury is reduction in inflammation. In fact, POC prevented complement activation and was associated with a reduced renal tissue tumor necrosis alpha (TNFalpha) level and myeloperoxidase activity in addition to a reduced cycloxygenase (COX)2/COX1 ratio [13]. Impact of POC on mitochondrial membrane integrity and function has also been investigated in several studies. Eldaif et al. [14] demonstrated that POC leads to activation of protein kinase C via adenosine and also modifies mitochondrial membrane permeability thereby improving cell survival. In addition, Zhang et al. [15] found that POC increases mitochondrial membrane potential, which reduces the formation of mitochondrial permeability transition pores (MPTP), a process that can lead to ROS production and apoptosis. Furthermore, these authors demonstrated that blockade of the mitochondrial KATP channels (mitoKATP) using 5-hydroxydecanoate diminished the salutary impact of POC on renal IRI, thereby implicating this channel in partly mediating the beneficial effects of POC [15]. In this issue of the journal Nephrology Dialysis Transplantation, Tan et al. [16] expand on the findings of the studies mentioned so far and convincingly demonstrate that POC ameliorates renal IRI by reducing mitochondrial oxidative stress. In addition, POC was shown to reduce mtDNA damage that occurs early in the course of renal IRI and might have contributed to mitochondrial dysfunction and apoptosis. In confirmation of the earlier studies, Tan et al. also found improved mitochondrial membrane potential in animals which underwent POC when compared with those in the IRI sham POC group. The authors further demonstrated that IRI was associated with a reduction in mitoKATP channel subunit, Kir6.2. This reduction might have led to a decreased influx of potassium into the cells and subsequent calcium overload, mitochondrial swelling and an opening of MPTP. These mitochondrial events are accompanied by disruption of mitochondrial membrane potential, increased ROS production and apoptosis [17]. Reduction in mitoKATP channel subunit, Kir6.2, was reversed by POC. In addition, the authors demonstrated that one potential mechanism that might explain the salutary effects of POC in renal IRI was activation of mitoKATP channels. There is mounting evidence which indicates that POC can be of significant value in the prevention and treatment of AKI. The potential clinical feasibility and utility of this intervention was demonstrated recently in a study by Deftereos et al. [18] of 225 patients with non-ST elevation myocardial infarction who underwent angiography and percutaneous coronary intervention. Patients were randomized to remote POC and control groups (remote POC = remote organ postischemia conditioning). The POC group underwent serial balloon inflation and deflations of one of their coronary arteries during PCI. Remote POC was associated with a significantly decreased risk of development of AKI in patients undergoing coronary angiography with a number needed to treat of 6 to prevent one episode of AKI. Although the experiments presented in this issue by Tan et al. provide important mechanistic explanations as to how POC can afford protection against renal IRI, further clinical studies are needed to translate these important laboratory findings into therapeutic interventions. Future studies need to determine a window of time during which POC implementation can be effective in alleviating renal IRI. In this study, the authors waited 7min after reperfusion prior to initiating POC; however, this can be difficult to replicate in the clinical setting given the unpredictable nature of ischemic insults. Furthermore, the potential role of remote POC (POC in a remote organ and not the kidney) needs to be further studied and delineated. Future studies should also address the need for non-invasive methods of delivering POC, which would provide the same benefits as those methods used in the laboratory and surgical setting.