Figure 3.

Global molecular axes invoked during AKI. Many interactions exist between endothelial cells, epithelial cells, and blood cells in the pathophysiology of AKI. These interactions are bidirectional between the cells involved, and result in specific functional and structural alterations. Inflammatory mediators released from proximal tubular cells influence endothelial cell processes (e.g. increased vasoconstriction and expression of cell adhesion molecules) that in turn interfere with and modulate endothelial cells, leading to reduced microvascular flow and continued hypoxia within the local environment. Co-occurring augmented ROS production within the cells and cross-signalling induces additional signalling events leading to oxidative stress. The impairment to replenish the intracellular ATP pool, as well as NAD depletion, of vascular and tubular cells is one of the major contributors to cell injury and tissue damage. Primary pathways which are involved in multifaceted AKI are delineated in gene activation cascades (blue arrows), signalling events (black arrows and inhibitions) and metabolic pathways (green arrows and inhibitions). Modulations are indicated as arrows (positive signalling events) or t-bars (inhibitions). Ultimate clinically observed end-points are marked in bold. Pharmacological intervention studies in inhibiting AKI or alleviate AKI-dependent symptoms by targeting specific molecules are indicated by inhibition of targets (red circles) or stimulation (green triangles).