Role of heme oxygenase-1 in autophagy modulation during ischemic renal injury

Abstract

The ischemic renal injury, the most common cause of acute kidney injury (AKI ) , is an insult characterized by sudden and transient decrease in renal blood flow, which is followed by a robust inflammatory process and a strong pro-oxidant response, as a consequence to hypoxia and reperfusion. Often, such damage is observed during septic shock, hepatorenal syndrome, cardiac transplantation or systemic hypoperfusion. Although in recent years we observed significant improvements in the health system, such renal disease is still associated with high mortality, especially in hospitalized patients. It is known that the response of renal tubule cells to ischemic injury depends on the intensity and duration of ischemia. Furthermore, many cellular phenomena such as proliferation, dedifferentiation, loss of cell polarity and cell death occur during the course of the disease . Although important discoveries have been made with regard to the definition of the biological effects of ischemic injury, there is few drugs available for this clinical problem. Thus, the search for new therapies that promote mechanisms of tissue resistance to such injuries can be critical to the resolution of the lesion process. In this sense, we highlight heme oxygenase-1 (HO-1), a key enzyme in the degradation of free heme and widely recognized to be responsible for the formation of end products like biliverdin (which is rapidly converted to bilirubin), carbon monoxide and free iron. These by-products appear to play important anti-inflammatory, anti-apoptotic, anti-oxidants and immunomodulatory functions. The basal levels of HO - 1 in the kidney are relatively low, but after some harmful stimuli we can observe a strong induction, predominantly in the proximal tubular region in order to promote rapid organ recovery. Corroborating this hypothesis, the data generated by our group demonstrated that the pharmacological induction of HO-1 was beneficial in different models of renal injury. Despite the progress made with regard to the elucidation of the molecular mechanisms involved in the adaptive response to subsequent renal insult, some aspects still need to be better understood in order to mitigate their harmful consequences. Thus, it is speculated that the induction of autophagy process could be highly a beneficial factor. Autophagy is a catabolic process involving the breakdown of cell components themselves through the lysosomal machinery, and , as a regulated process, has a constitutive role in cell growth, development and cellular homeostasis. Although autophagy is traditionally recognized as a cellular response to nutrient limitation, recent studies suggest that this process seems to play an important role in cellular response to stress, generating a strong pro- survival signal. Our preliminary data indicate that up-regulation of HO- 1 generates a pro- autophagy signaling in vivo and in vitro. Based on this, we hypothesized that the induction of HO - 1 would generate a cytoprotective signaling, which would be, at least partly, mediated by autophagy.