The effects of ischemic preconditioning on rat liver integrity, as well as the implication of nitric oxide (NO) and adenosine in this process, has been evaluated. Preconditioning before ischemia-reperfusion prevented the increases in alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels, but did not modify blood flow. Adenosine or NO administration previous to hepatic ischemia-reperfusion simulated the effect of preconditioning, whereas inhibition of adenosine or NO synthesis abolished the protective effect of hepatic preconditioning. Nevertheless, inhibition of adenosine and simultaneous administration of NO in preconditioned animals offered similar results to those found in the preconditioned group, indicating that, in the absence of adenosine, NO is able to maintain the preconditioning benefits. It is suggested that, in preconditioning, adenosine stimulates NO production to protect against the injury associated with ischemia-reperfusion.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease globally. The primary initiating mechanism in DN is hyperglycemia-induced vascular dysfunction, but its progression is due to different pathological mechanisms, including oxidative stress, inflammatory cells infiltration, inflammation and fibrosis. Macrophages (Mφ) accumulation in kidneys correlates strongly with serum creatinine, interstitial myofibroblast accumulation and interstitial fibrosis scores. However, whether or not Mφ polarization is involved in the progression of DN has not been adequately defined. The prevalence of the different phenotypes during the course of DN, the existence of hybrid phenotypes and the plasticity of these cells depending of the environment have led to inconclusive results. In the same sense the role of the different macrophage phenotype in fibrosis associated or not to DN warrants additional investigation into Mφ polarization and its role in fibrosis. Due to the association between fibrosis and the progressive decline of renal function in DN, and the role of the different phenotypes of Mφ in fibrosis, in this review we examine the role of macrophage phenotype control in DN and highlight the potential factors contributing to phenotype change and injury or repair in DN.

This study aims to determine if the protective role of adenosine in liver ischemic preconditioning is mediated by the activation of adenosine receptors and to ascertain which of these receptors is implicated in the process. Administration of adenosine A₁ and A₂ receptor antagonists to preconditioned animals indicates that hepatic preconditioning is mediated by the activation of adenosine A₂ receptors. Propentofylline (an inhibitor of adenosine transport into cells) in the preconditioned group, subjected to previous administration of an adenosine A₂ receptor antagonist, prevented the negative effect of the latter on the protection offered by preconditioning. An increase of NO production was detected just immediately after hepatic preconditioning, and the administration of an adenosine A₂ receptor antagonist to the preconditioning group prevented this increase, thus abolishing the protective effect of preconditioning. However, the administration of a NO donor to the preconditioned group subjected to previous administration of the adenosine A₂ receptor antagonist was able to maintain the preconditioning effects. In conclusion, these results indicate that, in preconditioning, the protective effect of adenosine could be a result of an increase in extracellular adenosine. This in turn would induce the activation of adenosine A₂ receptors, which, by eliciting an increase in NO generation, would protect against the injury associated with hepatic ischemia–reperfusion.

Macrophage infiltration is a common feature of the early phase of renal ischaemia/reperfusion injury. Indeed, it is generally regarded as the cause of tissue injury in this phase, although it is also clear that it can lead to tissue repair in other phases. In order to ascertain whether macrophages are directly involved in the repair/late phase, which follows the pro‐inflammatory and injury process of renal ischaemia/reperfusion, we used two different approaches based on macrophage depletion. Firstly, we produced renal ischaemia in mice that were previously treated with clodronate liposome. Secondly, during reperfusion we re‐injected RAW 264.7 to macrophage‐depleted mice 24 h prior to sacrifice. The results showed that regeneration, as evaluated by stathmin and PCNA markers, was macrophage‐dependent: it was blocked when macrophage depletion was provoked and recovered with macrophage re‐injection. The cytokine profile revealed the influence of the inflammatory environment on kidney repair: pro‐inflammatory cytokines (MCP‐1, MIP‐1α) increased during the early stages of reperfusion, coinciding with low regeneration, and the anti‐inflammatory cytokine IL‐10 increased during the longer periods of reperfusion when regeneration was more evident. We conclude that macrophages induce renal regeneration after ischaemia/reperfusion, depending on the inflammatory milieu. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.