The pathogenesis of acute kidney injury and the toxic triangle of oxygen, reactive oxygen species and nitric oxide.

Despite the identification of several of the cellular mechanisms thought to underlie the development of acute kidney injury (AKI), the pathophysiology of AKI is still poorly understood. It is clear, however, that instead of a single mechanism being responsible for its etiology, AKI is associated with an entire orchestra of failing cellular mechanisms. Renal microcirculation is the physiological compartment where these mechanisms come together and exert their integrated deleterious action. Therefore, the study of renal microcirculation and the identification of the determinants of its function in models of AKI can be expected to provide insight into the pathogenesis and resolution of AKI. A major determinant of adequate organ function is the adequate oxygen (O(2)) supply at the microcirculatory level and utilization at mitochondrial levels for ATP production needed for performing organ function. The highly complex architecture of the renal microvasculature, the need to meet a high energy demand and the borderline hypoxemic nature of the kidney makes it an organ that is highly vulnerable to injury. Under normal, steady-state conditions, the oxygen supply to the renal tissues is well regulated and utilized not only for mitochondrial production of ATP (mainly for Na reabsorption), but also for the production of nitric oxide and the reactive oxygen species needed for physiological control of renal function. Under pathological conditions, such as inflammation, shock or sepsis, however, the renal microcirculation becomes compromised, which results in a disruption of the homeostasis of nitric oxide, reactive oxygen species, and oxygen supply and utilization. This imbalance results in these compounds exerting pathogenic effects, such as hypoxemia and oxidative stress, resulting in further deterioration of renal microcirculatory function. Our hypothesis is that this sequence of events underlies the development of AKI and that integrated therapeutic modalities targeting these pathogenic mechanisms will be effective therapeutic strategies in the clinical environment.