Fig. 9.

Schematic drawing depicting the amplification of ROS-mediated responses by MIOX following AGE:RAGE interaction. Following AGE:RAGE interaction there is a generation of ROS, which leads to the transcriptional upregulation of MIOX, as well as activation of PKC. In addition, AGE:RAGE interaction leads to sequential activation and phosphorylation of various kinases, including PI3K, PDK, and AKT. They then phosphorylate various transcription factors with their translocation into the nucleus and target various genes that are responsible for profibrogenic and proinflammatory processes consequentially leading to fibrosing injury. As a sidearm of these signaling pathways, the activated kinases can phosphorylate MIOX, thereby increasing its enzymatic activity and cyclic generation of ROS. This pervasive generation of ROS leads to additional phosphorylation of transcription factors with amplification of transcription of target genes and worsening of fibrosing injury in the renal tubulointerstitial compartment, conceivably in settings of hyperglycemic or diabetic state. ECM, extracellular matrix. The drawing has taken into account the data of previous work of various authors (Refs. 38, 39, 47, 50, and 60).