Figure 2.

Molecular mechanisms of renal IRI. During ischemia, the lack of oxygen and substrates led to inhibition of oxidative phosphorylation, thereby to ATP depletion. From a side this led to an anaerobic lactic acid-associated glycolysis, with pH decrease and lysosome lytic enzyme release. From the other, the blockade of pump Na/K activated proteases and phospholipases, leading to increased Ca++ level. Furthermore, ATP produced in aerobic tissues is lysed into AMP, adenosine, inosine and hypoxanthine. Hypoxanthine is metabolized by xanthine oxidase in ischemic tissues, in a reaction that uses molecular oxygen (O₂) and release toxic ROS as intermediate products. During reperfusion, DAMP released by ischemic damaged kidney cells are recognized by PRR as TLR on immune cells but also on endothelial cells leading to increased gene expression of pro-inflammatory cytokines that recruited and activated leucocytes. These cells released more cytokines, in an amplification loop culminating into ROS release by macrophages and neutrophils, interstitial infiltrates and kidney damage. Ischemic damaged cells can activate complement system (by Collectin-11, MBL) that result in anaphylotoxins C3a and C5a generation and MAC-mediated cell injury. These acute processes have been linked to early renal fibrosis development by the process of EndMT, EMT and PMT (Endothelial to mesenchymal transition, Epithelial to mesenchymal transition and Pericytes to mesenchymal transition). TLR, Toll Like receptor; MAC, membrane associated complex; DAMP, Damage-associated molecular patterns; PRR, Pattern Recognition Receptors; ROS, reactive oxygen species.