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.

The present work investigates the relationship between adenosine, nitric oxide (NO), and free radicals during ischemic preconditioning in rat liver. For this purpose, we evaluated: 1) the efficacy of different periods of preconditioning; 2) the changes in the concentration of adenine nucleotides during preconditioning; 3) the importance of adenosine and xanthine concentrations in the induction of preconditioning; and 4) the possible effect of xanthine oxidase-derived superoxide anion on NO during preconditioning. Results show that just a 10-to 15-minute period of ischemia followed by 10-minute reperfusion prevents the ischemic damage that would be induced by a subsequent 90 minutes of ischemia followed by 90 minutes of reperfusion. Administration of xanthine or metabolization of endogenous adenosine abolishes the protective effect of preconditioning. When rats have been subjected to a period of preconditioning not within the effective time window (10-15 minutes), and thus offering no protection, the administration of a NO donor was found to restore the protection. The dose needed to restore protection appears to be proportional to the endogenous xanthine concentration. In addition, when xanthine oxidase was inhibited, preconditioning effectively offered protection in front of ischemia and reperfusion, independently of the xanthine concentration. Altogether, this indicates that the time window of ischemia capable to induce preconditioning in liver is defined by the relative tissue concentrations of adenosine and xanthine. The lower limit of this window (10 minutes) is defined by the amount of adenosine able to induce NO generation. Its upper limit (15 minutes) is defined by the concentration of xanthine able to remove the generated NO. (HEPATOLOGY 1998;28:768-773.)In 1986, Murry et al. discovered that short periods of ischemia and reperfusion render the myocardium resistant to a subsequent more-sustained ischemic insult. 1 This phenomenon, called ischemic preconditioning, has been commonly studied in the heart, but few studies have been performed on intestine 2 or liver. 3 The mechanism underlying preconditioning remains unknown and is currently under intense investigation. It has been suggested that protection depends on the release of substances by the organ helping to protect it against injury. Along this line, potential mediators include nitric oxide (NO) 2,4 and adenosine. 5 Vegh et al. 6 reported that the protection conferred by preconditioning in dog heart in vivo disappeared after NO inhibition. Nevertheless, other authors 7 found that endogenous NO is not a mediator in the ischemic preconditioning in the isolated rat heart. Recent work by our group, using a model of hepatic preconditioning in rat, demonstrated that inhibition of NO abolishes the effect of preconditioning. 8 In the same study, we suggested that NO production was stimulated by endogenous adenosine. It is known that pretreatment with adenosine or selective adenosine A 1 receptor agonists mimics the effect of preconditioning in heart. 10 Bot...