OBJECTIVE Alterations of the renal microcirculation can promote the development of acute kidney injury through the interlinked occurrence of renal hypoxia and activation of inflammatory pathways. This review focuses on the recent advances in this area, and discusses the possible therapeutic interventions that might be derived from these insights. RESULTS Endothelial injury acts as a primary event leading to renal hypoxia with disturbances in nitric oxide pathways playing a major role. The unbalanced homeostasis between nitric oxide, reactive oxygen species and renal oxygenation forms a major component of the microcirculatory dysfunction. Furthermore, injury leads to leukocyte-endothelial interaction that exacerbates renal hypoxia at a microcirculatory level. CONCLUSIONS Knowledge of the pathophysiological mechanisms of acute kidney injury emphasizes the importance of the role of the microcirculation in its development. Preventive and therapeutic approach should be based on restoring the homeostasis between nitric oxide, reactive oxygen species and renal oxygenation.