Observations | Proposed mechanisms |
---|---|
Glucotoxicity: IGT postprandial, IFG, and overt T2DM | Protein Kinase C (PKC) activation. Altered integrin expression of podocyte and pericyte: (podocyte-pericyte loss) |
Increased Synthesis Of: Type Iv Collagen | TGF beta, VEGF, and possibly PDGF beta 1. All associated with PKC activation and induction of growth hormones – factors from glucotoxicity and → ROS. |
Increased Maintenance of: type IV Collagen AGE cross-linking of type IV collagen. AGE – RAGE connection. | Increased resistance to protease (MMP) degradation, allowing type IV collagen to accumulate. |
Decreased Degradation. | Decreased MMP-2 MMP-3 |
Decreased Degradation. | Increased expression of TIMP-2 |
Increased ROS. In general, ROS promotes ECM fibrosis under the influence of chronic injurious stimuli and is associated with the chronic inflammatory state. | ROS increases all aspects of type IV accumulation: Glucotoxicity → PKC activation, AGE cross-linking activation, Decreased eNOS and eNO activity resulting in increased MMP activation.* |